Urological device

ABSTRACT

A urological device comprises a urological valve for location in the bladder of a patient and a valve support stem for location in the urethra of a patient. The valve has a normally closed configuration to prevent flow from the bladder and an open configuration for fluid flow through the valve. The valve is automatically movable from the closed configuration to the open configuration in response to a pre-set hydrodynamic pressure applied for a pre-set time. In one case the valve has a plurality of valve leaflets with a region of co-aption between the valve leaflets. In the normally closed configuration the valve leaflets are engaged at the region of co-aption and in the open configuration the leaflets are separated at the co-aption region for fluid flow through the valve.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of U.S. Patent ApplicationNo. 61/409,741 filed Nov. 3, 2010, U.S. patent application Ser. No.12/971,451 filed Dec. 17, 2010, and U.S. Patent Application No.61/553,489 filed Oct. 31, 2011, the entire contents of all of which areincorporated herein by reference.

INTRODUCTION

Prostate Cancer is the most common male malignancy in the Western world.In the U.S. there are approximately 180,000 new diagnoses annually. Eachyear, 40,000 men with established disease die from prostate cancer.

The main cause of stress urinary incontinence (SUI) in males is radicalprostatectomy for cancer. Catalona W J, Carvalhal G F, Mager D E, SmithD S. Potency, continence and complication rates in 1,870 consecutiveradical retropubic prostatectomies. J Urol. 1999 August; 162(2):433-8report that the incidence of SUI 1 yr post radical prostatectomy is 20%.

Lee W R, Schultheiss T E, Hanlon A L, Hanks G E. Urinary incontinencefollowing external-beam radiotherapy for clinically localized prostatecancer Urology. 1996 July; 48(1):95-9 report that adjuvant radiotherapyof prostate cancer can also affect treatment of SUI.

There is a need for a urology device that will improve patient qualityof life by effectively providing a patient controlled device thatremoves the need for a urine bag and also facilitates normal socialfunctioning.

STATEMENTS OF INVENTION

According to the invention there is provided a urological devicecomprising a urological valve for location in the bladder of a patientand a valve support stem for location in the urethra of a patient. Thevalve has a normally closed configuration to prevent flow from thebladder and an open configuration for fluid flow through the valve. Thevalve is automatically movable from the closed configuration to the openconfiguration in response to a pre-set hydrodynamic pressure applied fora pre-set time.

In one embodiment the valve support stem comprises a generally tubularsupport for extending at least partially through the urethra, the valvebeing located at one end of the support.

In one case the device comprises a bladder retainer for locating thevalve in the bladder.

The bladder retainer may comprise a flare extending radially outwardlyof the support stem.

The bladder retainer may be of the same material as that of the support.

In one embodiment the bladder retainer, the support and the valve areintegrally moulded.

The device may comprise stiffening means for the bladder retainer. Thebladder retainer stiffening means may be of a shape memory material suchas Nitinol.

In one embodiment the device comprises a urethral retainer to preventmigration of the device.

In one case the urethral retainer comprises a metal tab.

In one embodiment the urethral retainer comprises a bulbous region ofcompressive material.

According to the invention there is provided a urological devicecomprising a urological valve, the valve comprising a plurality of valveleaflets, the valve having a region of co-aption between the valveleaflets, the valve having a normally closed configuration in which thevalve leaflets are engaged at the region of co-aption and an openconfiguration in which the leaflets are separated at the co-aptionregion for fluid flow through the valve, the valve being automaticallymovable from the closed configuration to the open configuration inresponse to applied urological pressure.

In one embodiment the valve is of a viscoelastic polymeric foammaterial.

In one case the valve leaflets evert on movement between the closed andthe open configuration in response to applied urological pressure.

The valve may be adapted to open in response to a preset pressureapplied over a preset time. The valve may be adapted to open in responsea pressure of at least 750 mm H₂O applied for at least 5 seconds.

In one embodiment the valve is adapted to remain closed in response to aspike pressure applied for a short time as would be generated by a usercoughing. The spike pressure may be 900 mm H₂O applied for a period ofless than 0.5 seconds.

In one embodiment the valve remains open as fluid flows therethroughwithout a requirement for a user to apply urological pressure. The valvemay return to the closed configuration when flow through the valve hassubstantially stopped.

In one case the valve everts on movement from the closed to openconfiguration. The valve may revert on return from the open to theclosed configuration.

In one embodiment the valve comprises at least three valve leaflets.There may for example be six valve leaflets.

The valve may comprise a main body having a region which defines a hingeabout which portion of the valve main body is movable between the closedand open configurations.

In one embodiment the valve comprises stiffening means. The hinge regionmay be at least partially defined adjacent to the stiffening means.

In one embodiment the urological device comprises a support for thevalve. The support may be generally cylindrical. In one case the supportis of the same material as that of the valve. In one embodiment thevalve and support are integrally moulded.

The urological device may comprise a first retainer for locating thedevice in the bladder. The first retainer may comprise a flare extendingradially outwardly of the support. The first retainer may be of the samematerial as that of the support.

In one case the first retainer, the support and the valve are integrallymoulded.

The urological device may comprise stiffening means for the firstretainer. The retainer stiffening means may be of a shape memorymaterial such as Nitinol.

In one embodiment the urological device comprises a second retainer toprevent proximal migration of the device. The second retainer maycomprise a metal tab. The second retainer may comprise a bulbous regionof compressive material.

In one embodiment the urological device comprises an antimicrobialcoating.

In one case the device comprises a support to which the valve ismounted. The support may be adapted for mounting in a urinary tract. Thesupport may comprise a generally tubular member.

The tubular member may comprise a catheter.

In one embodiment the urological device comprises an anchor foranchoring the support and valve in situ.

In some cases the device comprises a housing for the valve, the housinghaving an inlet on one side of the valve and an outlet on the oppositeside of the valve. The inlet may be adapted for mounting to a cathetersuch as a Foley catheter. The outlet may be adapted for mounting to adrainage bag.

In one case the urological device comprises a collar to support thevalve in the housing. The valve may comprise a valve body and the collaris arranged to engage the valve body to control the pressure at whichthe valve moves from the open to the closed configuration and/or fromthe closed to the open configuration.

The invention also provides a drainage catheter system comprising avalve, the valve having:—

-   -   a normally closed configuration in which the valve is closed;        and    -   an open configuration in which the valve is opened for flow        through the valve;    -   the valve being automatically movable from the closed to the        open configuration for flushing of the catheter.

The valve may be a one-way valve. The valve may be movable from theclosed to the open position in response to a predefined yield pressure.The valve may be of a biocompatible viscoelastic foam material.

In one case the catheter comprises a urological catheter.

According to the invention there is provided a urological devicecomprising a urological valve having:—

-   -   a normally closed configuration in which the valve is closed;        and    -   an open configuration in which the valve is opened for flow        through the valve;    -   the valve being movable from the closed to the open        configuration in response to applied urological pressure.

In one embodiment the device comprises a support to which the valve ismounted.

In one case the support is adapted for mounting in a urinary tract.

The support may comprise a generally tubular member. The tubular membermay comprise a catheter.

In one embodiment the device comprises an anchor for anchoring thesupport and valve in situ.

In one aspect the valve everts on movement between the closed and theopen configuration in response to applied urological pressure. Onreduction of urological pressure to a preset pressure the valve returnsfrom the open to the closed configuration.

In another aspect the device comprises a housing for the valve, thehousing having an inlet on one side of the valve and an outlet on theopposite side of the valve. The inlet may be adapted for mounting to acatheter such as a Foley catheter. The outlet may be adapted formounting to a drainage bag.

In one embodiment the device comprises a collar to support the valve inthe housing. The valve may comprise a valve body and the collar isarranged to engage the valve body to control the pressure at which thevalve moves from the open to the closed configuration and/or from theclosed to the open configuration.

In one embodiment the valve is adapted to open in response to a presetpressure applied over a preset time. The valve may be adapted to remainclosed in response to a spike pressure applied for a short time such aswould be generated by a user coughing.

The invention also provides a drainage catheter system comprising avalve, the valve having:—

-   -   a normally closed configuration in which the valve is closed;        and    -   an open configuration in which the valve is opened for flow        through the valve;    -   the valve being automatically movable from the closed to the        open configuration for flushing of the catheter.

In one embodiment the valve is a one-way valve. The valve may be movablefrom the closed to the open position in response to a predefined yieldpressure. The valve may be of a biocompatible viscoelastic foammaterial.

In one embodiment the valve comprises a polymeric valve body having anouter support rim, at least three valve leaflets, and a main body regionextending between the support rim and the valve leaflets.

The invention also provided a luminal valve for placing in a body lumencomprising at least four valve leaflets, the valve having a normallyclosed configuration in which the leaflets are engaged and an openconfiguration in which the leaflets are open. There may be at least fivevalve leaflets. There may be six valve leaflets.

The valve may comprise a valve body of polymeric material. The valve maycomprise an outer support region. The valve may also have a main bodyregion extending between the support region and the valve leaflets.

In one case the main body region is generally concave between the outersupport rim and a region of co-aption of the valve leaflets.

In one case the valve leaflets have a region of co-aption and the valvebody is reinforced at the region of co-aption. The valve body may bethickened at the region of co-aption.

The region of co-aption may extend for an axial length of at least 1 mm.The region of co-aption may extend for a depth of from 1 mm to 5 mm.

In one embodiment the support rim of the valve body is reinforced. Thesupport rim of the valve may be thickened. In one embodiment the valvecomprises three valve leaflets. In another embodiment the valvecomprises six valve leaflets.

In one embodiment the polymeric material is stable to gastric fluid forat least 3 months, for at least 4 months, for at least 5 months, for atleast 6 months, for at least 7 months, for at least 8 months, for atleast 9 months, for at least 10 months, for at least 11 months, or forat least one year.

In one case the polymeric material takes up less than about 5%, lessthan about 10%, less than about 15%, less than about 20%, less thanabout 25%, or less than about 30% by weight of water at equilibrium.

In one case the polymeric material of the valve body has a % elongationof from 50% to 3000% or 200% to 1200%.

In one case the polymeric material of the valve body has a tensilestrength of from 0.01 to 5 MPa or about 0.1 to 1.0 MPa, or about 0.25 to0.5 MPa.

In one embodiment the polymeric material has a Young's Modulus of about0.01 to 0.6 MPa, or about 0.1 to about 0.5 MPa.

In one embodiment the polymeric material of the valve body has a densityof from 0.1 g/cm³ to 1.5 g/cm³, or 0.3 to 1.2 g/cm³, or 0.8 to 0.9g/cm³, or 0.5 to 0.6 g/cm³.

In one embodiment the distance between the proximal end of the supportregion of the valve body and the distal end of the valve leaflets isless than 50 mm, or less than 40 mm, or less than 30 mm, or less than 25mm, or less than 20 mm, or less than 15 mm.

In one case the polymeric material of the valve body is of an elasticmaterial.

In another case the polymeric material of the valve body is of aviscoelastic material.

In one embodiment the polymeric material of the valve body comprises afoam. The polymeric material of the valve body may comprise an open cellfoam.

In one embodiment the polymeric material of the valve body comprises apolyurethane foam.

In one embodiment the length of the valve from the proximal end of thesupport region to the distal end of the valve leaflets is less than 50mm, less than 40 mm, less than 30 mm. The length of the valve may beapproximately the same as the outer diameter of the support region ofthe valve. The length of the valve may be approximately 23 mm.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be more clearly understood from the followingdescription thereof given by way of example only, in which:—

FIG. 1 is an isometric view (from above) of a urological valve accordingto the invention;

FIG. 2 is an isometric view (from below) of the valve of FIG. 1;

FIG. 3 is an underneath plan view of the valve;

FIG. 4 is a top plan view of the valve;

FIGS. 5 and 6 are isometric, partially cut-away sectional, views of thevalve;

FIGS. 7 and 8 are cross sectional views of the valve;

FIG. 9 is a cross sectional view of the valve in a normally closedconfiguration with a force F1 applied;

FIG. 10 is a cross sectional view of the valve in an open configurationin response to the force F1;

FIG. 11 is a cross sectional view of the valve returned to the closedconfiguration after opening to flow;

FIG. 12 is a cross sectional view of the valve in a normally closedconfiguration with a force F2 applied;

FIG. 13 is a cross sectional view of the valve in an open configurationin response to the force F2;

FIG. 14 is a cross sectional view of the valve returned to the closedconfiguration after opening;

FIG. 15 is an isometric view (from above) of the valve in a normallyclosed configuration;

FIG. 16 is an isometric view of the valve moving towards an openconfiguration in response to the force F1;

FIG. 17 is an isometric view of the valve in a fully open configurationpermitting flow;

FIG. 18 is an isometric view (from below) of the valve in a normallyclosed configuration;

FIG. 19 is an isometric view of the valve in a partially openconfiguration in response to the force F2;

FIG. 20 is an isometric view of the valve in a fully open configurationin response to force F2;

FIG. 21 is an isometric view of another valve according to theinvention;

FIG. 22 is a cross sectional view of the valve in a closedconfiguration;

FIG. 23 is a cross sectional view with the valve in the openconfiguration in response to a urological pressure F1;

FIG. 24 is an elevational view of the valve of FIG. 21;

FIG. 25 is a plan view of the device of FIG. 21 with the valve in aclosed configuration;

FIG. 26 is a plan view similar to FIG. 25 with the valve in an openconfiguration;

FIG. 27 is an isometric view of an external urological valve deviceaccording to the invention;

FIG. 28 is another isometric view of the device of FIG. 27;

FIG. 29 is an isometric, partially cut-away view of the device of FIGS.27 and 28 with a valve omitted;

FIG. 30 is an exploded view of the device of FIGS. 27 and 28;

FIGS. 31 to 33 are elevational, partially cross sectional viewsillustrating the device of FIGS. 27 to 30 in use with the valve indifferent configurations;

FIG. 34 is a graph of pressure over time illustrating the pressureapplied when the valve is in the configurations of FIGS. 31 to 33;

FIGS. 35 and 36 are cross sectional views of the device of FIGS. 29 to34 illustrating eversion of the valve and fluid flow;

FIGS. 37 to 39 are elevational, partially cross sectional views of thedevice of FIGS. 29 to 33 and 35 to 36 in use illustrating thefunctioning of the valve in use when exposed to a rapid pressure spike;

FIG. 40 is a graph of pressure over time illustrating the pressureapplied when the valve is in the configuration of FIGS. 37 to 39;

FIG. 41 is a cross sectional view illustrating a valve mountingarrangement;

FIG. 42 is an isometric view of a collar used for mounting the valve;

FIG. 43 is a cross sectional view of the collar of FIG. 42;

FIG. 44 is an isometric view of the device of FIGS. 27 to 33 mounted toa catheter;

FIG. 45 is a cross sectional view illustrating a male version device andcatheter in use;

FIG. 46 is an enlarged view of a detail of FIG. 45;

FIG. 47 is a cross sectional view of a female version of the device andcatheter in use;

FIG. 48 is an enlarged view of a detail of FIG. 47;

FIG. 49 is a cross sectional view illustrating a modified male versionof the device and catheter in use;

FIG. 50 is an enlarged view of a detailed of FIG. 49;

FIG. 51 is a cross sectional view illustrating a modified female versionof the device and catheter in use;

FIG. 52 is an enlarged view of a detail of the device of FIG. 51;

FIG. 53 is a view of a prior cut drainage catheter;

FIG. 54 is an enlarged cross sectional view of detail A of FIG. 53;

FIG. 55 is an enlarged cross sectional view of detail B of FIG. 53;

FIG. 56 is a view of a drainage catheter according to the invention insitu, the catheter having a valve in a closed configuration;

FIG. 57 is a cross sectional view of detail B of FIG. 56;

FIG. 58 is a view of the catheter and valve of FIG. 56 with the valve inan open configuration;

FIG. 59 is an enlarged cross sectional view of detail A of FIG. 58;

FIG. 60 is an enlarged cross sectional view of detail B of FIG. 58;

FIG. 61 is a graph of time taken for devices to encrust using anaccelerated bacterial culture test;

FIG. 62 is a cross sectional view illustrating another female version ofthe device;

FIG. 63 is an enlarged view of a detail of the device of FIG. 62;

FIG. 64 is a cross sectional view of an internal urological valve devicein use;

FIG. 65 is an enlarged view of a detail of FIG. 64;

FIG. 66 is a cross sectional view of another internal urological valvedevice in use;

FIG. 67 is an enlarged view of a detail of FIG. 66;

FIG. 68 is a perspective view of another valve device according to theinvention;

FIG. 69 is a cross sectional view of the valve device of FIG. 68;

FIG. 70 is a cross sectional view of the valve device of FIGS. 68 and 69in situ in a bladder neck;

FIGS. 71 to 73 are diagrams illustrating the delivery and deployment ofa valve device according to the invention;

FIG. 74 is a cross sectional view of another valve device of theinvention deployed in a bladder neck;

FIG. 75 is a cross sectional view illustrating the opening of a valve atthe proximal end of the device of FIG. 74 opening in response topressure;

FIG. 76 is a perspective view of another valve device according to theinvention;

FIG. 77 is a cross sectional view of the device of FIG. 76;

FIG. 78 is a perspective view of another valve device according to theinvention;

FIG. 79 is a cross sectional view of the device of FIG. 78;

FIG. 80 is a cross sectional view of the device of FIGS. 78 and 79anchored in a bladder neck;

FIG. 81 is a perspective view of another valve device according to theinvention;

FIG. 82 is a cross sectional view of the device of FIG. 81;

FIG. 83 is a cross sectional view of the device of FIGS. 81 and 82 inuse;

FIG. 84 is a cross sectional view of another valve device according tothe invention, in use;

FIG. 85 is a perspective view of another urological device according tothe invention;

FIG. 86 is a cut-away view of the device of FIG. 85;

FIG. 87 is a cross sectional view of the device of FIGS. 85 and 86;

FIG. 88 is an enlarged view of a detail of FIG. 87;

FIG. 89 is a perspective view of a further urological device accordingto the invention;

FIG. 90 is a perspective view of a further urological device accordingto the invention;

FIG. 91 is a cut-away view of the device of FIG. 90;

FIG. 92 is a cross sectional view of the device of FIG. 91;

FIG. 93 is an enlarged view of a detail of FIG. 92;

FIG. 94 is a graph illustrating the flow characteristics through aurological device of the invention;

FIG. 95 is a graph of the pressure profile of a urological device of theinvention during accelerated bladder filling simulation;

FIG. 96 is a graph of differential pressure control using a urologicaldevice of the invention;

FIG. 97 is an illustration of prior art polymers with urea and urethanelinkages interspersed between homopolymer soft segments;

FIG. 98 is an illustration of a polyurethane/urea foam according to theinvention with urea and urethane linkages interspersed between triblockcopolymer soft segments;

FIG. 99 is an illustration of a siloxane and polypropylene oxide basedtriblock copolymer in different forms;

FIG. 100 is a graph of comparative mechanical properties of homo(VF130309) and triblock copolymer (VF230209A) soft segments;

FIG. 101 is a graph of comparative mechanical properties of home(VF190309) and triblock copolymer (VF090309) soft segments;

FIG. 102 is a graph illustrating the mechanical performance of triblockcopolymer soft segments versus homopolymer soft segment duringaccelerated aging in simulated gastric fluid;

FIG. 103 depicts a gastric yield pressure test apparatus as utilized inExample 10;

FIG. 104 and FIG. 105 depict results of accelerated stability of a valveprepared from a viscoelastic foam of the present invention;

DETAILED DESCRIPTION

Referring to the drawings and initially to FIGS. 1 to 20 thereof thereis illustrated a urological valve 1 which can open automatically inresponse to applied urological pressure.

The valve 1 comprises a polymeric valve body having an outer supportregion with a rim 2, at least three valve leaflets 3, 4, 5, and a mainbody region 6 extending between the support rim 2 and the valve leaflets3, 4, 5. The valve leaflets 3, 4, 5 extend inwardly and terminate at endfaces 7, 8, 9 respectively. The leaflets each 3, 4, 5 have legs a, bwhich extend at an included angle of 120° to each other. The adjacentpairs of legs 3 a; 4 a; 4 b; 5 b; 5 a; 3 b; co-apt to close the gapbetween the valve leaflets when the valve is in the normally closedconfiguration.

The first configuration of the valve is a normally closed configurationin which the valve leaflets 3, 4, 5 co-apt to close the valve. Thesecond configuration is an open configuration to allow fluid flow inwhich the valve leaflets 3, 4, 5 are opened such that the leaflet legpairs 3 a; 4 a; 4 b; 5 b; 5 a; 3 b are opened and spaced-apart inresponse to a force F1 to allow flow through the valve.

The valve can also be opened in response to an external force F2, forexample as might be applied if a medical instrument such as a catheteris passed therethrough.

The various configurations of the valve 1 are illustrated in FIGS. 11 to20. In the first or normally closed configuration (FIGS. 9, 15) thevalve leaflets 3, 4, 5 co-apt.

When a urological pressure force F1 is applied to the valve body. Thisforce initially pushes the valve leaflets 3, 4, 5 against one anotherand if the pressure is greater than a set value, the valve body willinvert. The start of inversion is illustrated in FIG. 16. When the valveis fully opened in response to force F1 the valve main body (and theleaflets 3, 4, 5) extend downwardly as illustrated in FIGS. 10 and 17.This allows flow to pass through the valve. When the flow is stopped thevalve main body will return to the original configuration by everting inresponse to the biasing of the polymeric material to return to thenormally closed configuration with the valve leaflets extending asillustrated in FIGS. 11 and 15.

When force F2 is applied to the valve leaflets 3, 4, 5 the leaflet legspairs 3 a; 4 a; 4 b; 5 b; and 5 a; 3 b open to allow an object such as amedical instrument to pass (FIGS. 13, 20). FIG. 19 illustrates apartially open configuration in response to a force F2. When theinstrument is withdrawn the force F2 is removed and the leaflets 3, 4, 5return to the closed position under the inherent biasing of thepolymeric material of the valve body (FIG. 13).

The valve leaflets 3, 4, 5 are reinforced in the region of co-aption. Inthis case, this is achieved by a local thickening of the polymericmaterial in this region. Similarly the support rim 2 is reinforced by alocal thickening of the polymeric material.

The region of co-aption of the valve leaflets 3, 4, 5 has an axialextent which is typically from 1 to 5 mm. This ensures positiveco-aption of the leaflets across a significant interfacial area when thevalve is in the normally closed configuration. The thickness of theleaflets at the region of co-aption is typically between 0.1 mm and 10mm.

By varying the properties (such as density) of the material of the valvethe valve can be tailored to accommodate varying yield pressures. Thevalve accomplishes this by controllably inverting when placed underpressure.

The valve 1 of the invention returns to its original working positionafter being fully opened. This is accomplished without damaging theworking valve.

When the valve is opened by an applied urological pressure and fluidflow the leaflets open. The outer face of the valve has a greaterresistance to change in shape and thus the force required to open mainbody in this direction is higher.

The important characteristics influencing the functioning of the valveare the leaflet legs that impinge on one another. By varying thegeometry and length of the leaflets 3, 4, 5 the valve 1 can be made toopen in one direction at different pressures. Opening in the oppositedirection is somewhat less dependant on the geometry of the leaflets andmore dependant on the elasticity and density of the material the deviceis made from. Additionally, the overall diameter and the diameter towhich the leaflets open influence the opening force in both directions.

The valve may be of any suitable biocompatible polymeric material. Itmay be of a biocompatible polymeric material having properties whichallow the valve to function as described.

The materials used for the production of this valve have a % elongationbetween 50% and 3000%. The material also has a tensile strength ofbetween 0.01 and 5 MPa. Additionally the material could have anantimicrobial action to prevent colonisation when in-vivo. Additionallythe material can be elastic or viscoelastic and can optionally be anopen cell foam. The density of the material should be between 0.1 g/cm³to 1.5 g/cm³.

The valve may have any desired number of leaflets, for example the valve30 illustrated in FIGS. 21 to 26 has six valve leaflets 251. Theseleaflets 251 are oriented perpendicular to direction of flow toadditionally allow greater distensibility of the valve aperture.

The valve 30 is similar to the valve described above and comprises apolymeric valve body having a proximal outer support region with a rim32, six valve leaflets 33, and a main body region 36 extending betweenthe support rim 32 and the valve leaflets 33. The valve leaflets 33extend terminate at distal end faces 33. The leaflets each have legswhich extend at an included angle of 60° to each other. The adjacentpairs of legs co-apt to close the gap between the valve leaflets 33 whenthe valve is in the normally closed configuration.

The first configuration of the valve 30 is a normally closedconfiguration in which the valve leaflets 33 co-apt to close the valve.The second configuration is an open configuration to allow fluid flow inwhich the valve leaflets 33 are opened such that the leaflet leg pairsare opened and spaced-apart in response to a force F1 to allow flowthrough the valve 30. The valve can also be opened in response to anexternal force F2, for example as might be applied if a medicalinstrument such as a catheter is passed therethrough.

The various configurations of the valve 30 are illustrated in FIGS. 21to 26. In the first or normally closed configuration (FIG. 21) the valveleaflets 33 co-apt.

When a urological pressure force F1 is applied to the valve body. Thisforce initially pushes the valve leaflets 33 against one another (FIG.22) and if the pressure is greater than a set value, the valve body willinvert as illustrated in FIG. 23. When the valve is fully opened inresponse to force F₁ the valve main body (and the leaflets 33) extenddownwardly as illustrated in FIG. 23. This allows flow to pass throughthe valve. When the flow is stopped the valve main body will return tothe original configuration by everting in response to the biasing of thepolymeric material to return to the normally closed configuration withthe valve leaflets extending as illustrated in FIG. 21.

FIG. 26 illustrates a partially open configuration in response to aforce F2. When the instrument is withdrawn the force F2 is removed andthe leaflets 33 return to the closed position under the inherent biasingof the polymeric material of the valve body.

The valve leaflets 33 are reinforced in the region of co-aption. In thiscase, this is achieved by a local thickening of the polymeric materialin this region. Similarly the support rim 32 is reinforced by a localthickening of the polymeric material.

The region of co-aption of the valve leaflets 33 has an axial extentwhich is typically from 1 to 5 mm. This ensures positive co-aption ofthe leaflets across a significant interfacial area when the valve is inthe normally closed configuration. The thickness of the leaflets at theregion of co-aption is typically between 0.1 mm and 10 mm.

The valve 30 requires different forces to open in the differentdirections. By varying the properties (such as density) of the materialof the valve the valve can be tailored to accommodate varying yieldpressures. The valve 30 accomplishes this by controllably inverting whenplaced under pressure. The valve 30 of the invention returns to itsoriginal working position after being fully opened. This is accomplishedwithout damaging the working valve.

One important characteristic influencing the functioning of the valve 30is the leaflet legs that impinge on one another. By varying the geometryand length of the leaflets 33 the valve 30 can be made to open in onedirection at different pressures. Opening in the opposite direction issomewhat less dependant on the geometry of the leaflets and moredependant on the elasticity and density of the material the device ismade from. Additionally, the overall diameter and the diameter to whichthe leaflets open influence the opening force in both directions.

The valve may be of any suitable biocompatible polymeric material. Itmay be of a biocompatible polymeric material having properties whichallow the valve to function as described.

The materials used for the production of this valve have a % elongationbetween 50% and 3000%. The material also has a tensile strength ofbetween 0.01 and 5 MPa. Additionally the material could have anantimicrobial action to prevent colonisation when in-vivo. Additionallythe material can be elastic or viscoelastic and can optionally be anopen cell foam. The density of the material should be between 0.1 g/cm³to 1.5 g/cm³.

Referring to FIGS. 27 to 58 of the drawings there are illustratedvarious urological valve devices according to the invention. The devicescomprise a valve 600 which may be of the type described above. The valvehas a normally closed configuration in which the valve is closed and anopen configuration in which the valve is opened for flow through thevalve. The valve is movable from the closed to the open configuration inresponse to applied urological pressure. In some cases the valve 600everts on movement between the closed and open configuration in responseto applied urological pressure. On reduction of urological pressure to apresent pressure the valve 600 returns from the open to the closedconfiguration. The device may be adapted for use in the male or femaleanatomy. In some cases the valve is mounted to a support. The supportmay be adapted for mounting in the urinary tract in which case there maybe an anchor for anchoring the valve in situ. The valve may be externalof the body and may be mounted in a housing having an inlet and anoutlet. The inlet may be adapted for mounting to a catheter such as aFoley catheter. The outlet may be adapted for mounting to a drainagemeans such as a bag or the like.

The invention provides a urological valve device that may be used totreat patients with stress urinary incontinence, for example as a resultof a radical prostatectomy. The valve will open based on the pressureapplied by the patient through the muscles of the bladder.

In one embodiment the device is for connection to a catheter such as aFoley catheter. The device in this configuration is not intended to bein direct contact with the urethra.

The continence mechanism of the device is a one-way valve that maintainsa leak-free system until a pre-defined hydraulic pressure is applied.Once the ‘break-pressure’ has been reached the lumen of the catheter isopen to drain freely. The lumen will remain open until fluid flow hasstopped after which the valve will reset itself (this may takes approx15 sec after cessation of micturition).

The valve is designed to open when a preset pressure applied to it. Thevalve is capable of remaining closed at higher pressures if they are notsustained for a prolonged period of time. For example, the valve can beopened by applying a pressure of 750 mmH₂O for 5 sec but should remainclosed during an pressure of 900 mmH₂O over a short time. The valve inthis way is insulated from coughing/straining related pressure spikes.

FIGS. 27 and 28 illustrate an external urological valve assembly housingwith a fitting 602 for connecting to a Foley catheter at proximal endand a fitting 601 for connecting to a drainage bag at distal end. Thehousing comprises a proximal section 604 and a distal section 603, whichare separable for insertion of a valve 600.

FIG. 29 is a cutaway view of the valve housing without a valve in place.The proximal and distal caps 603, 604 can be seen. An area 609 forseating the valve 600 is illustrated. There is an extended collar 610,which protrudes into the proximal lumen of the valve.

FIG. 30 is an exploded view of valve housing and valve 600, illustratinghow the extended collar 610 on the distal cap 602 locates into the lumenof the valve 600.

FIGS. 31 to 33 illustrates the functioning of the valve 600 under theinfluence of hydrostatic pressure. Referring to FIG. 31 as the urethralfluid pressure begins to rise the valve 600 starts to deform slightly.At a predetermined pressure the valve 600 will completely evert thusproviding a conducting path for fluid to pass. (FIG. 32) After apredetermined period of time the everted valve 600 will reorient itselfto its original position. (FIG. 33) This is graphically illustrated inFIG. 34.

FIGS. 35 and 36 illustrate valve eversion and fluid flow.

FIGS. 37 to 39 illustrate the functioning of the valve 600 when thevalve 600 is exposed to a rapid pressure spike. (FIG. 38) due to a coughor a sneeze may deform momentarily but unless the pressure is maintainedwill revert to its original configuration. (FIG. 39) In this situationthe valve 600 would require a predetermined prolonged time at highpressure to open the valve 600. This is graphically illustrated in FIG.40.

Referring to FIGS. 41 to 43 the mounting of the valve 600 may becontrolled using a separate collar component 650 having a projectingpart 651 which extends into the rim of the valve body to control thepressure at which the valve 600 moves from the open to the closedconfiguration and/or from the closed to the open configuration. This canbe varied by adjusting the length X of the projection 651. For example,a short length may allow the valve to freely move whereas longer lengthswould control the movement of the valve between the closed and openconfigurations. In this way a single valve may be used for a number ofdifferent applications by adjusting the projection 651 lengthappropriately.

FIGS. 44 to 48 illustrate embodiments of the use of the urology valveattached to a urinary catheter, such as a Foley catheter 620.

FIGS. 49 to 52 are views similar to FIGS. 44 to 48 illustrating analternative arrangement in which the valve device is incorporated intothe proximal housing of the urinary catheter.

The urological valve devices of the invention are in certain embodimentsmade from a polymeric viscoelastic material. The use of this materialaddresses a number of problems associated with conventional devices. Inthe prior art, urological devices have been made from metals andmaterials that are relatively stiff. These prior art devices, whenplaced in contact with soft tissues can lead to tissue remodelling,whereby the tissue can become eroded or fibrotic and hardened. Inaddition, the use of hard materials in contact with soft tissues canresult in irritation and subsequently discomfort for the patient.

The urological devices of the invention have features which functionusing polymeric viscoelastic materials. The viscoelastic polymericmaterials form valves, which are normally closed but which can evert onexposure to pressure. The mechanism by which the valves evert isassociated with the ability of the material to deform under pressure.The deformation of viscoelastic materials under pressure can also beinfluenced by the duration over which the pressure is applied.

The material used for may be as described below. The material may alsobe as described in our US2011-0152395A the entire contents of which areherein incorporated by reference.

The various urological valves described herein may be manufactured froma suitable polymeric viscoelastic material such as described below inexample 5 of the material section.

Valves of the type illustrated in FIGS. 28/29 above manufactured fromthis material were tested for opening pressure and flowrate. Thefollowing results were obtained.

Polymer Opening Valve Density Leakage pressure Flowrate Number (g/ml)(mls) (mmH2O) (ml/min) 1 1.02 0 817 877 2 0.95 0 703 894 3 1.01 0 877875 4 1.01 0 803 941 5 1.02 0 877 892 6 0.96 0 820 928 7 1.07 0 945 1010

The results in the table above illustrate that a number of valves madewith a density between 0.95-1.07 g/ml have opening pressures within therequired specification but with no leakage when the valve is closed. Theflowrate through the valve is also noteworthy as this enables bladderemptying within a reasonable timeframe.

This invention also relates to improvements in devices such as cathetersthat present a conduit through which bacteria can enter the internalanatomy. In particular, the invention relates to urological drainagecatheters. However, the technology described below may also be relevantto long and short term drainage devices such as supra pubic catheters,Percutaneous Endoscopic Gastrostomy (PEG) tubes and other devices thatmight present a conduit through which bacteria could enter the internalanatomy.

Bacteria external to the body are known to travel rapidly up the urethraleading to urinary tract infections and biofilm formation in the case ofindwelling catheters and devices.

The proliferation of Proteus Miribellis within urological devicesresults in the precipitation of salts and minerals from urine resultingin the ultimate encrustation of the device lumen leading to blockage.Although many attempts have been made to use antimicrobial coating toprevent this effect, no long term solution has been found and urinarycatheters will become blocked within a 3-4 week period.

The Foley urinary catheter has remained unchanged for the past 60 years.It is widely accepted that 100% of indwelling Foley catheters willbecome encrusted and block within a 4 week timeframe. A great deal ofcommercial effort has focused on increasing the longevity of thesedevices because long term users require specialist nurses to change thedevices frequently, which is costly.

There are very large number of disclosures in the prior art teaching theuse of a variety of antimicrobial coatings and inserts for use indrainage catheters. U.S. Pat. No. 4,603,152 describes antimicrobialcoatings for catheters canulea and the like. U.S. Pat. No. 7,601,361describes durable antimicrobial coatings. U.S. Pat. No. 4,932,948describes antimicrobial insert for a male urinary catheter. U.S. Pat.No. 5,782,808 describes an antimicrobial tubing connector.

One problem with the existing technology is that most of theantimicrobial agents are only minimally effective at preventing theproliferation of bacteria and the subsequent encrustation of drainagedevices by those bacteria. In addition many of the antimicrobial agentsin use can lead to the development of resistance by the bacteria to theagent in use.

Much work has been carried out to coat indwelling catheters withantimicrobial coatings in an effort to prevent biofilm formation. Thesecoatings have either been ineffective or of insufficient durability tosustain the antimicrobial effect.

Referring to FIGS. 53 to 55 there is illustrated a conventional urinarydrainage catheter 500 for draining urine from a bladder 501. Thecatheter comprises a tube 502 having an inlet 503 and an outlet 504through which urine is drained. The catheter 500 has a bulbous head 505for retaining the catheter in situ in the bladder. A conventionalcatheter of this type is generally referred to as a Foley catheter. Inuse, urine drips from the catheter outlet 504 into a collection bag.Such a catheter suffers from the considerable disadvantage thatbacterial colonisation and encrustation adjacent to the inlet 503 and inthe catheter lumen can occur, as illustrated in FIGS. 54 and 55respectively.

In the invention, a drainage catheter 550 has a valve 551 to controlflow through the catheter. FIGS. 56 and 57 illustrate the catheter 550when the valve 551 is in a closed configuration. The valve 551 allowsthe bladder to fill above the level of the catheter inlet 503. While thevalve 551 is closed a build up of urine in the catheter lumen may startthe process of bacterial biofilm formation and encrustation asillustrated in FIG. 57.

Referring to FIGS. 58 to 60 when the valve 551 is opened voluntarily apressurised flow of urine through the catheter is generated until thelevel of urine in the bladder 501 drops below the level of the catheterinlet 503. Regular application of such pressurised flow generatessufficient force to prevent accumulation of bacterial biofilm at thecatheter inlet and in the catheter lumen as illustrated in FIG. 59 andFIG. 60 respectively.

In the invention a one way valve is incorporated into a catheter,especially a urinary catheter. The valve is designed not to leak but toopen at a predefined yield pressure and return to its closed positionfollowing bladder emptying. The predefined yield pressure may correspondto an abdominal force generated by the patient through consciousstraining or due to normal movement. The force of standing or sittingalone is known to generate significant abdominal pressures. The valve inthis case is designed to be placed in line between the catheter and aurine collection bag. The valve facilitates the cyclic filling andemptying of the bladder and thus regular flushing of the catheter lumen.The emptying of the bladder may be conscious or unconscious due tomovement.

This invention teaches a completely different approach to thatconventionally used to achieve an antimicrobial effect. In the inventiona physical and mechanical means is used to achieve an antimicrobialeffect, thus avoiding the need for potentially cytotoxic coatings. Inaddition this approach represents a durable and sustained effect ratherthan the transient effect seen with antimicrobial compounds.

Accelerated microbial tests (FIG. 61) have demonstrated thatincorporation of a tricuspid valve of a biocompatible foam material asdescribed herein into a Foley catheter prolongs the ‘time toencrustation’ by a factor of almost 4 compared to an open Foleycatheter. The valve of the invention also performs very significantlybetter than a catheter fitted with a ball valve which is manuallymovable between an open and close configuration. One search prio-artvalve is available under the tradename FlipFlow.

The invention provides a valve for control of urinary incontinence. Thevalve opens at a specific bladder pressure, in one case when the bladderis full (or at a required volume), without any manual manipulation. Thebladder will then empty into an attached drainage bag and the valve willreturn to the closed position. This has the benefit of being easy touse. The use of a valve to offer intermittent rather than continualdrainage has been shown to potentially reduce catheter blockage. Thoseusers most likely to suffer from catheter blockages are those that haveother co-morbidities, a number of which result in dexterity or mobility.

The valve aids patients who are unable to use a conventional cathetervalve but who would still benefit greatly in maintaining ‘normal’bladder function by intermittent drainage as opposed to continuousdrainage.

In vitro studies in a laboratory model of the catheterised bladder wereundertaken to investigate the time to blockage of the valve of theinvention in comparison to the ‘Flip-flo’ (Trade Mark of Bard Inc) valveand continuous drainage model. The bladder model is described by Strikeret al in Stickler, D. J., Morris, N. S, and Winters, C. (1999). Simplephysical model to study formation and physiology of biofilms on urethralcatheters. Methods in Enzymology, 310:494.

The valve of the invention demonstrated a significantly increased lengthof time to blockage versus a continuous drainage model (110.4 vs. 22.9hours, p-value 0.001). There was no significant difference between anormally draining ‘Flip-flo’ valve and a ‘Flip-flo’ valve assisted bythe automated syringe pump (40.0 vs. 45.1 hours, p-value-0.425). Themean time to blockage was 110.4 hours for the valve of the inventioncompared to 45.1 hours for the automated Flip-flo: This result washighly significant (p-value 0.004).

The bladder model consists of a glass chamber (the bladder) maintainedat 37° C. by a water jacket. Each model was sterilised by autoclavingand then a size 14ch Romed catheter, latex based was inserted into thebladder chamber through a section of silicon tubing (the urethra) at thebase of the model. Catheters were secured in place at the outlet of thebladder by inflation of their balloons with 10 ml of deionised water.Where appropriate, the end of the catheters were then attached to eithera valve of the invention, Flip-flo valve or left open for continuousdrainage. The Flip-flo valve and the continuous drainage models werethen subsequently connected to drainage bags in the normal way but thevalve of the invention and automated Flip-flo valve were left to draininto a covered plastic beaker (to allow for an open system due to thepressures applied from the syringe pump). Sterile urine was pumped intothe chambers so that residual volumes collected below the cathetereye-holes before flowing through the drainage tube to the collectionbags/beaker.

Flip-flo valves were attached to normal Foley catheters with and withoutan automated syringe pump and intermittently opened every four hoursover a 12 hour period and then both switched to continuous drainageovernight, until blockage occurred. In normal use, a Flip-flo valvewould be used for intermittent drainage during the daytime andcontinuous drainage at night. This regime was used in the tests toreproduce normal use as much as possible.

Valved catheters according to the invention provide the patient with anumber of advantages: firstly unsightly drainage bags do not have to becontinually worn throughout the day, and secondly it also helps retainsome bladder tone because the bladder fills and empties periodically, asis the case in a ‘normal’ bladder. Additionally the periodic flushing ofurine through the catheter displaces some of the developing biofilm,which ultimately causes catheter blockage, and hence increases thelife-span of the catheter. The Vysera valve offers additional benefits,such as increasing the number of potential users to include those withdexterity or mobility difficulties and increase the life-span of thecatheter by permitting intermittent drainage to occur overnight as wellas during the day.+

FIGS. 62 to 65 illustrate a urology valve in an indwelling valve device600 to be retained using a balloon 630 or other anchor in the bladder.The valve 600 may be mounted to a tubular support 635. There may be apending tether 631 for recovery of the valve 600 externally.

FIGS. 66 and 67 illustrate a urology valve 600 in a self retainingstructure 635 placed in the urethra. This could be held in placed withan adhesive or through anchoring or suturing technology.

The continence mechanism of the body lies within the urethra. Theurethral closure mechanism consists of the external sphincter and thebladder neck (or internal sphincter). When contracted, these cause abouta 40 mm length of the urethra to be sealed.

In a closed or obstructed urethra any increase in abdominal pressure,due to straining, acts on the outside of the bladder and on the bladderneck. In a normal continent patient, because these pressures are equalbut acting oppositely no leakage occurs during the storage phase (whenthe bladder is filling).

The voiding or micturition phase begins with relaxation of the internalforces that close the urethra, specifically external sphincterrelaxation and opening of the bladder neck. This is followed by detrusormuscle contraction, which creates hydrodynamic pressure in the bladderleading to urine flow. Importantly, the hydrodynamic pressure in thebladder does not influence the opening of the bladder neck or theexternal sphincter [Paul Abrams, Urodynamics, Third Edition, Springer,page 13].

During micturition, when the urethra and bladder neck are fully open,the application of abdominal pressure only influences the bladder walland not the urethra or bladder neck. It is widely acknowledged that theonly effect of abdominal pressure application during unimpededmicturition is to increase hydrodynamic pressure within the bladder thusincreasing flow rate [Paul Abrams, Urodynamics, Third Edition, Springer,pages 84-85].

If the urethra is partially obstructed, application of abdominalpressure will influence both the sealing of the bladder neck andpressurising of the outside of the bladder. The net effect in this caseis to oppose the hydrodynamic pressure within the bladder and thusprevent flow.

Many technologies have been developed to address intraurethral failureand in general they have been focused on improving the seal within theurethra. An example of this is the use of collagen injections into thebladder neck to bulk up the internal sphincter mechanism.

U.S. Pat. No. 6,063,119 and U.S. Pat. No. 5,989,288 describe augmentingthe closure of the internal sphincter mechanism by positioning aprosthesis at the region of the upper urethra and bladder neck. Thesedevices act to seal the urethra when the normal anatomical forcescompress the outside of the bladder neck and urethra to prevent leakage.

In contrast, in this invention a urological valve is located in thebladder and is not impacted by the pressures in the urethra. Indeed, thevalve does not require any anatomical forces to maintain a seal, itopposes the pressure of the urine in the bladder. When abdominal restingpressure is acting on the outside of the bladder the valve provides anopposing pressure commensurate with the hydrodynamic pressure of theurine. When coughing occurs during the storage phase the opposingpressure exerted by the valve increases to match the rapid and shorthigh-pressure pulses due to coughing. When the patient chooses to void,the application of a relatively low pressure for a prolonged durationcauses the opposing force from the valve to slowly diminish andultimately disappear to generate hydrodynamic flow.

In the invention a prosthesis is placed inside the bladder. Theprosthesis has a valve, which is located at the end of a tubular conduitthat holds it in position and traverses the bladder neck and externalsphincter. The tubular conduit can be soft or resilient or can be softwith reinforced regions that are resistant to collapse. The conduitportion can allow urine to flow through its center.

The tubular conduit can also have a contoured region or regions locatedalong its external surface to help retain it in the urethra. Thesecontoured regions could be in the form of a bulbous structure designedto be located at the membranous urethra in the male anatomy to preventproximal migration. Alternatively the contours may be provided by aflared structure to conform to the female meatus to prevent proximalmigration.

The valve also has a circumferential flared region that is contoured tofit against the bladder wall. This region provides a means of sealingsuch that urine does not flow around the outside of the valve and isdirected through the valve. In addition this flared region could bereinforced with nitinol wire or polymeric fibers to improve resistanceto distal migration. Alternatively the flared region could be a balloon.

In-situ, the prosthesis prevents urine flow when the valve is closed.The valve opens when the urine in the bladder exceeds a pre-definedhydrodynamic pressure for a prolonged period of time (a typical range is690-900 mmH2O for 10 sec). Due to the prolonged time requirement thevalve will not open when exposed to pressures for shorter durations,even significantly higher pressures will not open the valve. For examplea sneeze or cough could apply sufficient pressure around the outside ofthe bladder to generate a hydrodynamic pressure within the bladder of1200-1600 mmH2O but since this would only be sustained for 0.5-1 secondor even cycled repeatedly the valve will remain closed.

The conduit, if soft, does not in any way augment the urethra. However,it may be desirable to make the conduit from a resilient material suchthat the urethra is kept open both at the internal and externalsphincter. This would in turn mean that continence would be entirelydependent on the in-bladder valve. In the case where the conduit isresilient at the region of the internal and external sphincters, wherebythe normal anatomical forces could not cause the urethra to be closed, avalve could be placed in the conduit that opens under similarhydrostatic pressures to the in-bladder valve.

Referring to FIGS. 68 to 70 there is illustrated another valve device800 according to the invention. The device 800 comprises a hollow stem801 and a head part 802 having slits 803 therein forming valve leaflets.When the slits 803 open in response to applied pressure, urine flowsthrough the head part 802 and into a flow channel 804 extending throughthe stem 801. The stem 801 also has a bulbous part 805 to assist inlocating and retaining the device in situ within a bladder neck 806.

FIGS. 71 to 73 illustrate the delivery and deployment of a valve device810 having a head part 811 with a valve 812 and a stem part 813. Thedelivery system comprises a catheter 820 which is advanced into the neckof the bladder. The valve device 810 is retained within the catheter 820in a retracted configuration (FIG. 71). The device 810 is deployed fromthe distal end 821 of the catheter (FIG. 72). During deployment thevalve device 810 expands to a deployed configuration and the catheter820 is withdrawn to deploy the proximal end of the device (FIG. 73).

FIGS. 74 and 75 illustrate the functioning of the valve device 810deployed in the bladder neck. The valve 812 at the proximal end opens inresponse to applied pressure.

FIGS. 76 and 77 illustrate a valve device 830 which is similar to thedevice of FIGS. 71 to 75. In this case there is a tab 831 at the distaltip of the device to ensure that the device is firmly located in situ.The tab 831 typically anchors at the meatus to prevent proximalmigration into the bladder.

Referring to FIGS. 78 to 80 there is illustrated another valve device850 according to the invention which in this case has anchoring tabs 851for anchoring the device in the bladder neck. In this case a valve part852 is located in the urethra.

Referring to FIGS. 81 to 83 there is illustrated another valve device860 according to the invention. The device 860 comprises a valve part861, a head part 862, and a stem part 863. The stem part 863 has a softcompressible foam structure 864 that anchors in the membranous urethra.

Referring to FIG. 84 there is illustrated another valve device 870according to the invention. The valve device 870 has a stem port 871with a deformable foam bulb 872. The bulb 872 acts as a valve and has anormally closed configuration. Application of a predefined pressurecauses the valve to open.

Referring to FIG. 85 to 86 there is illustrated another urologicaldevice 900 according to the invention. In this case the device is foruse in a male. The device 900 comprises a valve 901 at one end of atubular stem 902. The device has a bladder retainer comprising a flaredregion 903 which is typically of 40 mm diameter for a valve diameter of9 mm. The device also has a second retainer in this case provided by abulbous region 904 for maintaining the position of the device in theurethra.

The valve 901 is in this case of a polymeric viscoelastic foam materialand is of the type described above with reference to FIGS. 1 to 20.

In this case the leaflets are at the top of the device and the valve hasa stiffening means provided by vertical reinforcement features 905 whichdefine a fulcrum or hinge region about which the valve leaflets aremovable from a normally closed configuration as illustrated in FIGS. 85to 88 to an open position. The valve has a region of co-aption betweenthe valve leaflets and has a normally closed configuration in which thevalve leaflets are engaged at the region of co-aption and an openconfiguration in which the leaflets are separated at the co-aptionregion for fluid flow through the valve. The valve is movableautomatically from the closed to the open configuration in response toapplied urological pressure. In this case the leaflets evert on movementbetween the closed and the open configuration in response to userpatient applied urological pressure. The valve is adapted to open inresponse to a preset pressure applied over a preset time. For example,the valve may be adapted to open in response to a pressure of at least750 mm H₂O applied for at least 5 seconds. However, the valve remainsclosed in response to a spike pressure applied for a short time such aswould be generated by a user coughing. The valve remains open as fluidflows therethrough without a requirement for a user to continue to applyurological pressure. The flow through the valve is sufficient to keepthe valve open. The valve returns to the closed configuration when flowthrough the valve has substantially stopped. The valve in this caseeverts on movement from the closed to the open configuration and revertson movement from the open to the closed configuration.

In this case the valve and the other elements of the device are all of apolymeric viscoelastic foam material. For example, for optimisedmanufacturing and cost the device may be integrally moulded.

The various urological devices of the invention may comprise a suitableanti-microbial agent such as an anti-microbial coating.

Referring to FIG. 89 there is illustrated another urological device 910which is similar to the device of FIGS. 85 to 88 and like parts areassigned the same reference numerals. In this case the retaining flare903 is reinforced, for example by a mesh 911 which may, for example beof a shape memory material such as Nitinol.

Referring to FIGS. 90 to 93 there is illustrated another urologicaldevice 920 according to the invention which is similar to the device ofFIGS. 85 to 88 and like parts are assigned the same reference numerals.In this case he device is for female use and the retaining meanscomprises a metal tab 921 for prevention of proximal migration.

Test Results

Various tests were carried out using the urological devices of theinvention. The following relates in particular to a female urologicaldevice as illustrated in FIG. 90 and described above. The device wasmanufactured from a polymeric foam material as described in Example 5below. The valve was a 9 mm valve

Referring to FIG. 94 the flow characteristics through a urologicaldevice of the invention is illustrated. It can be seen that flow throughthe valve is maintained even when the pressure is very low. This featureensures that emptying of the bladder can be completed withoutmaintaining constant urological or abdominal pressure.

Referring to FIG. 95 the pressure profile of a urological device of theinvention is illustrated during simulated bladder pressure ramp. It canbe seen that until a certain pressure is exerted on the valve the valvedoes not open. Further the pressure continues to drop even after theinitial depressurization of the valve due to opening. This in turnillustrates a similar point to FIG. 94 in that constant application ofelevated pressure is not required to keep the valve open.

Referring to FIG. 96 differential pressure control using a urologicaldevice of the invention is illustrated. In this illustration the firstpeak shows the normal opening of the valve due to application ofelevated pressure. The magnitude of pressure required to trigger thevalve in this case is indicative of a prolonged application or rampingof pressure or valsalva maneuver. The second set of peaks illustratesthe application of high pressure spikes to the valve to simulatecoughing. In the case of coughing the valve does not open.

The following section describes one group of biomaterials that aresuitable for manufacturing devices and valves of the invention.

The material may also be as described in our US2011-0152395A the entirecontents of which are herein incorporated by reference.

Use of polyethers as soft segments in polyurethane foams is know toresult in soft elastic and viscoelastic materials due to the dynamicreinforcing effect of hydrogen bonding. Conversely, use of non-hydrogenbonding hydrophobic soft segments results in harder, less elasticmaterial. Blending of such hydrophobic and hydrophilic homopolymer softsegments as shown in FIG. 85 via urethane/urea linkages is known in theart to achieve mechanical properties appropriate to specificapplications.

Acid catalysed hydrolytic degradation occurs at urethane linkages withinpolyurethane materials. These urethane/urea linkages are therefore the‘weak-links’ of the polyurethane material. It follows that the intrinsichydrophilicity of the polyurethane material will affect the rate ofhydrolysis through modulation of water uptake. Thus, such materials areincompatible with use in a gastric environment (i.e., a highly acidicaqueous environment).

Thus, in some embodiments, the present invention provides a multiblockcopolymer that is biomimetic and hydrolytically stable in a gastricenvironment. Such multiblock copolymers are of formula I:

wherein:each

represents a point of attachment to a urethane or urea linkage;each of X and Y is independently a polymer or co-polymer chain formedfrom one or more of a polyether, a polyester, a polycarbonate, or afluoropolymer;each of R¹, R², R³, R⁴, R⁵ and R⁶ is independently selected from one ormore of R, OR, —CO₂R, a fluorinated hydrocarbon, a polyether, apolyester or a fluoropolymer;each R is independently hydrogen, an optionally substituted C₁₋₂₀aliphatic group, or an optionally substituted group selected fromphenyl, 8-10 membered bicyclic aryl, a 4-8 membered monocyclic saturatedor partially unsaturated heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, or sulphur, or 5-6membered monocyclic or 8-10 membered bicyclic heteroaryl group having1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;each of m n and p is independently 2 to 100; andeach of L¹ and L² is independently a bivalent C₁₋₂₀ hydrocarbon chainwherein 1-4 methylene units of the hydrocarbon chain are optionally andindependently replaced by —O—, —S—, —N(R)—, —C(O)—, —C(O)N(R)—,—N(R)C(O)—, —SO₂—, —SO₂N(R)—, —N(R)SO₂—, —OC(O)—, —C(O)O—, or a bivalentcycloalkylene, arylene, heterocyclene, or heteroarylene, provided thatneither of L¹ nor L² comprises a urea or urethane moiety.

2. DEFINITIONS

Compounds of this invention include those described generally above, andare further illustrated by the classes, subclasses, and speciesdisclosed herein. As used herein, the following definitions shall applyunless otherwise indicated. For purposes of this invention, the chemicalelements are identified in accordance with the Periodic Table of theElements, CAS version, Handbook of Chemistry and Physics, 75^(th) Ed.Additionally, general principles of organic chemistry are described in“Organic Chemistry”, Thomas Sorrell, University Science Books,Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th) Ed.,Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, theentire contents of which are hereby incorporated by reference.

As described herein, compounds of the invention may optionally besubstituted with one or more substituents, such as are illustratedgenerally above, or as exemplified by particular classes, subclasses,and species of the invention. It will be appreciated that the phrase“optionally substituted” is used interchangeably with the phrase“substituted or unsubstituted.” In general, the term “substituted”,whether preceded by the term “optionally” or not, refers to thereplacement of hydrogen radicals in a given structure with the radicalof a specified substituent. Unless otherwise indicated, an optionallysubstituted group may have a substituent at each substitutable positionof the group, and when more than one position in any given structure maybe substituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. The term “stable”, as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and preferablytheir recovery, purification, and use for one or more of the purposesdisclosed herein. In some embodiments, a stable compound or chemicallyfeasible compound is one that is not substantially altered when kept ata temperature of 40° C. or less, in the absence of moisture or otherchemically reactive conditions, for at least a week.

The term “aliphatic” or “aliphatic group”, as used herein, denotes ahydrocarbon moiety that may be straight-chain (i.e., unbranched),branched, or cyclic (including fused, bridging, and spiro-fusedpolycyclic) and may be completely saturated or may contain one or moreunits of unsaturation, but which is not aromatic. Unless otherwisespecified, aliphatic groups contain 1-20 carbon atoms. In someembodiments, aliphatic groups contain 1-10 carbon atoms. In otherembodiments, aliphatic groups contain 1-8 carbon atoms. In still otherembodiments, aliphatic groups contain 1-6 carbon atoms, and in yet otherembodiments aliphatic groups contain 1-4 carbon atoms. Suitablealiphatic groups include, but are not limited to, linear or branched,alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as(cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

The term “lower alkyl” refers to a C₁₋₄ straight or branched alkylgroup. Exemplary lower alkyl groups are methyl, ethyl, propyl,isopropyl, butyl, isobutyl, and tert-butyl.

The term “lower haloalkyl” refers to a C₁₋₄ straight or branched alkylgroup that is substituted with one or more halogen atoms.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR⁺ (as in N-substituted pyrrolidinyl)).

The term “unsaturated”, as used herein, means that a moiety has one ormore units of unsaturation.

As used herein, the term “bivalent C₁₋₈ [or C₁₋₆] saturated orunsaturated, straight or branched, hydrocarbon chain”, refers tobivalent alkylene, alkenylene, and alkynylene chains that are straightor branched as defined herein.

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(n)—, wherein n is apositive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylenegroup in which one or more methylene hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “alkenylene” refers to a bivalent alkenyl group. A substitutedalkenylene chain is a polymethylene group containing at least one doublebond in which one or more hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “halogen” means F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic orbicyclic ring systems having a total of five to fourteen ring members,wherein at least one ring in the system is aromatic and wherein eachring in the system contains 3 to 7 ring members. The term “aryl” may beused interchangeably with the term “aryl ring”.

As described herein, compounds of the invention may contain “optionallysubstituted” moieties. In general, the term “substituted”, whetherpreceded by the term “optionally” or not, means that one or morehydrogens of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a suitable substituent at each substitutable position ofthe group, and when more than one position in any given structure may besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. The term “stable”, as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and, in certainembodiments, their recovery, purification, and use for one or more ofthe purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently halogen;—(CH₂)₀₋₄R^(∘); —(CH₂)₀₋₄OR^(∘); —O—(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄CH(OR^(∘))₂; —(CH₂)₀₋₄SR^(∘); —(CH₂)₀₋₄Ph, which may besubstituted with Ro; —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which may be substituted withR^(∘); —CH═CHPh, which may be substituted with R^(∘); —NO₂; —CN; —N₃;—(CH₂)₀₋₄N(R^(∘))₂; —(CH₂)₀₋₄N(R^(∘))C(O)R; —N(R^(∘))C(S)R^(∘);—(CH₂)₀₋₄N(R)C(O)NR^(∘) ₂; —N(R^(∘))C(S)NR^(∘) ₂;—(CH₂)₀₋₄N(R^(∘))C(O)OR^(∘); —N(R^(∘))N(R^(∘))C(O)R^(∘);—N(R^(∘))N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))N(R^(∘))C(O)OR^(∘);—(CH₂)₀₋₄C(O)R^(∘); —C(S)R^(∘); —(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄C(O)SR^(∘); —(CH₂)₀₋₄C(O)OSiR^(∘) ₃; —(CH₂)₀₋₄OC(O)R^(∘);—OC(O)(CH₂)₀₋₄SR—, SC(S)SR^(∘); —(CH₂)₀₋₄SC(O)R^(∘); —(CH₂)₀₋₄C(O)NR^(∘)₂; —C(S)NR^(∘) ₂; —C(S)SR^(∘); —SC(S)SR^(∘), —(CH₂)₀₋₄OC(O)NR^(∘) ₂;—C(O)N(OR^(∘))R^(∘); —C(O)C(O)R^(∘); —C(O)CH₂C(O)R^(∘);—C(NOR^(∘))R^(∘); —(CH₂)₀₋₄SSR^(∘); —(CH₂)₀₋₄S(O)₂R^(∘);—(CH₂)₀₋₄S(O)₂OR^(∘); —(CH₂)₀₋₄OS(O)₂R^(∘); —S(O)₂NR^(∘) ₂;—(CH₂)₀₋₄S(O)R^(∘); —N(R^(∘))S(O)₂NR^(∘) ₂; —N(R^(∘))S(O)₂R^(∘);—N(OR^(∘))R^(∘); —C(NH)NR^(∘) ₂; —P(O)₂R^(∘); —P(O)R^(∘) ₂; —OP(O)R^(∘)₂; —OP(O)(OR^(∘))₂; SiR^(∘) ₃; —(C₁₋₄ straight or branchedalkylene)O—N(R^(∘))₂; or —(C₁₋₄ straight or branchedalkylene)C(O)O—N(R^(∘))₂, wherein each R^(∘) may be substituted asdefined below and is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur, or, notwithstanding the definition above, twoindependent occurrences of R^(∘), taken together with their interveningatom(s), form a 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, which may be substituted as definedbelow.

Suitable monovalent substituents on R^(∘) (or the ring formed by takingtwo independent occurrences of R^(∘) together with their interveningatoms), are independently halogen, —(CH₂)₀₋₂R^(•), -(haloR^(•)),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(•), —(CH₂)₀₋₂CH(OR^(•))₂; —O(haloR^(•)), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(•), —(CH₂)₀₋₂C(O)OH, —(CH₀₋₂C(O)OR,—(CH₂)₀₋₂SR^(•), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(•),—(CH₂)₀₋₂NR^(•) ₂, —NO₂, —SiR^(•) ₃, —OSiR^(•) ₃, —C(O)SR^(•)—(C₁₋₄straight or branched alkylene)C(O)OR^(•), or —SSR^(•) wherein each R^(•)is unsubstituted or where preceded by “halo” is substituted only withone or more halogens, and is independently selected from C₁₋₄ aliphatic,—CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. Suitable divalent substituents on asaturated carbon atom of R^(•) include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))₂₋₃O—, or—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic which may be substituted as defined below,or an unsubstituted 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR*₂)₂₋₃O—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen,—R^(•), -(haloR^(•)), —OH, —OR^(•), —O(haloR^(•)), —CN, —C(O)OH,—C(O)OR^(•), —NH₂, —NHR^(•), —NR^(•) ₂, or —NO₂, wherein each R^(•) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which may be substitutedas defined below, unsubstituted —OPh, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(†), taken together with their intervening atom(s) form anunsubstituted 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(†) are independentlyhalogen, —R^(•), -(haloR^(•)), —OH, —OR^(•), —O(haloR^(•)), —CN,—C(O)OH, —C(O)OR^(•), —NH₂, —NHR^(•), —NR^(•) ₂, or —NO₂, wherein eachR^(•) is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

3. DESCRIPTION OF EXEMPLARY EMBODIMENTS

A. Multiblock Copolymers

As described generally above, one embodiment of the present inventionprovides a triblock copolymer of formula I:

wherein the copolymers are chemically interspersed (bound) betweenurethane and/or urea linkages (i.e., at the bond designated with

and wherein each of X, Y, m, n, p, L¹, L², R¹, R², R³, R⁴, R⁵, and R⁶ isas defined and described herein.

As defined generally above, the each of X and Y groups of formula I isindependently a polymer or co-polymer chain formed from one or more of apolyether, a polyester, a polycarbonate, and a fluoropolymer.

Examples of polymer or co-polymer chains represented by X and/or Yinclude: poly(ethylene oxide), poly(difluoromethyl ethylene oxide),poly(trifluoromethyl ethylene oxide), poly(propylene oxide),poly(difluoromethyl propylene oxide), poly(propylene oxide),poly(trifluoromethyl propylene oxide), poly(butylene oxide),poly(tetramethylene ether glycol), poly(tetrahydrofuran),poly(oxymethylene), poly(ether ketone), poly(etherether ketone) andcopolymers thereof, poly(dimethylsiloxane), poly(diethylsiloxane) andhigher alkyl siloxanes, poly(methyl phenyl siloxane), poly(diphenylsiloxane), poly(methyl di-fluoroethyl siloxane), poly(methyltri-fluoroethyl siloxane), poly(phenyl di-fluoroethyl siloxane),poly(phenyl tri-fluoroethyl siloxane) and copolymers thereof,poly(ethylene terephthalate) (PET), poly(ethylene terephthalate ionomer)(PETI), poly(ethylene naphthalate) (PEN), poly(methylene naphthalate)(PTN), poly(butylene teraphalate) (PBT), poly(butylene naphthalate)(PBN), polycarbonate.

In certain embodiments, the present invention provides a pre-formed softsegment for a polyurethane/urea foam.

In some embodiments X is a polyether and Y is a polyether. Morespecifically in one case X and Y are both poly(propylene oxide).

In certain embodiments, m and p are each independently between 2 and 50and n is between 2 and 20. In some embodiments, m and p are eachindependently between 2 and 30 and n is between 2 and 20.

As defined generally above, each of R¹, R², R³, R⁴, R⁵ and R⁶ isindependently selected from one or more of R, OR, —CO₂R, a fluorinatedhydrocarbon, a polyether, a polyester or a fluoropolymer. In someembodiments, one or more of R¹, R², R³, R⁴, R⁵ and R⁶ is —CO₂R. In someembodiments, one or more of R¹, R², R³, R⁴, R⁵ and R⁶ is —CO₂R whereineach R is independently an optionally substituted C₁₋₆ aliphatic group.In certain embodiments, one or more of R¹, R², R³, R⁴, R⁵ and R⁶ is—CO₂R wherein each R is independently an unsubstituted C₁₋₆ alkyl group.Exemplary such groups include methanoic or ethanoic acid as well asmethacrylic acid and other acrylic acids.

In certain embodiments, one or more of R¹, R², R³, R⁴, R⁵ and R⁶ isindependently R. In some embodiments, one or more of R¹, R², R³, R⁴, R⁵and R⁶ is an optionally substituted C₁₋₆ aliphatic group. In certainembodiments, one or more of R¹, R², R³, R⁴, R⁵ and R⁶ is an optionallysubstituted C₁₋₆alkyl. In other embodiments, one or more of R¹, R², R³,R⁴, R⁵ and R⁶ is an optionally substituted group selected from phenyl,8-10 membered bicyclic aryl, a 4-8 membered monocyclic saturated orpartially unsaturated heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, or sulphur, or 5-6membered monocyclic or 8-10 membered bicyclic heteroaryl group having1-4 heteroatoms independently selected from nitrogen, oxygen, orsulphur. Exemplary such R¹, R², R³, R⁴, R⁵ and R⁶ groups include methyl,ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, cyclobutyl,phenyl, pyridyl, morpholinyl, pyrrolidinyl, imidazolyl, and cyclohexyl.

In certain embodiments, one or more of R¹, R², R³, R⁴, R⁵ and R⁶ isindependently —OR. In some embodiments, one or more of R¹, R², R³, R⁴,R⁵ and R⁶ is —OR wherein R is an optionally substituted C₁₋₆ aliphaticgroup. In certain embodiments, one or more of R¹, R², R³, R⁴, R⁵ and R⁶is —OR wherein R is C₁₋₆alkyl. In other embodiments, one or more of R¹,R², R³, R⁴, R⁵ and R⁶ is —OR wherein R is an optionally substitutedgroup selected from phenyl, 8-10 membered bicyclic aryl, a 4-8 memberedmonocyclic saturated or partially unsaturated heterocyclic ring having1-2 heteroatoms independently selected from nitrogen, oxygen, orsulphur, or 5-6 membered monocyclic or 8-10 membered bicyclic heteroarylgroup having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulphur. Exemplary such R¹, R², R³, R⁴, R⁵ and R⁶ groupsinclude -Omethyl, -Oethyl, -Opropyl, -Oisopropyl, -Ocyclopropyl,-Obutyl, -Oisobutyl, -Ocyclobutyl, -Ophenyl, -Opyridyl, -Omorpholinyl,-Opyrrolidinyl, -Oimidazolyl, and -Ocyclohexyl.

In certain embodiments, one or more of R¹, R², R³, R⁴, R⁵ and R⁶ isindependently R wherein each R is a C₁₋₆ aliphatic group substitutedwith one or more halogens. In some embodiments, each R is C₁₋₆ aliphaticsubstituted with one, two, or three halogens. In other embodiments, eachR is a perfluorinated C₁₋₆ aliphatic group. Examples of fluorinatedhydrocarbons represented by R¹, R², R³, R⁴, R⁵ and R⁶ include mono-,di-, tri, or perfluorinated methyl, ethyl, propyl, butyl, or phenyl. Insome embodiments, each of R¹, R², R³, R⁴, R⁵ and R⁶ is trifluoromethyl,trifluoroethyl, or trifluoropropyl.

In certain embodiments, one or more of R¹, R², R³, R⁴, R⁵ and R⁶ isindependently a polyether. Examples of polyethers represented by R¹, R²,R³, R⁴, R⁵ and R⁶ include poly(ethylene oxide), poly(difluoromethylethylene oxide), poly(trifluoromethyl ethylene oxide), poly(propyleneoxide), poly(difluoromethyl propylene oxide), poly(propylene oxide),poly(trifluoromethyl propylene oxide), poly(butylene oxide),poly(tetramethylene ether glycol), poly(tetrahydrofuran),poly(oxymethylene), poly(ether ketone), poly(etherether ketone) andcopolymers thereof.

In certain embodiments, one or more of R¹, R², R³, R⁴, R⁵ and R⁶ isindependently a polyester. Examples of polyesters represented by R¹, R²,R³, R⁴, R⁵ and R⁶ include poly(ethylene terephthalate) (PET),poly(ethylene terephthalate ionomer) (PETI), poly(ethylene naphthalate)(PEN), poly(methylene naphthalate) (PTN), poly(butylene teraphalate)(PBT), poly(butylene naphthalate) (PBN), polycarbonate.

In certain embodiments, one or more of R¹, R², R³, R⁴, R⁵ and R⁶ isindependently a fluoropolymer. Examples of fluoropolymers represented byR¹, R², R³, R⁴, R⁵ and R⁶ include poly(tetrafluoroethylene), poly(methyldi-fluoroethyl siloxane), poly(methyl tri-fluoroethyl siloxane),poly(phenyl di-fluoroethyl siloxane).

In some embodiments, R¹, R², R³, R⁴, R⁵ and R⁶ is independentlyhydrogen, hydroxyl, carboxylic acids such as methanoic or ethanoic acidas well as methacrylic acid and other acrylic acids. Alkyl or arylhydrocarbons such as methyl, ethyl, propyl, butyl, phenyl and ethersthereof. Fluorinated hydrocarbons such as mono-, di-, tri, orperfluorinated methyl, ethyl, propyl, butyl, phenyl. Polyether such asPoly(ethylene oxide), poly(difluoromethyl ethylene oxide),poly(trifluoromethyl ethylene oxide), poly(propylene oxide),poly(difluoromethyl propylene oxide), poly(propylene oxide),poly(trifluoromethyl propylene oxide), poly(butylene oxide),poly(tetramethylene ether glycol), poly(tetrahydrofuran),poly(oxymethylene), poly(ether ketone), poly(etherether ketone) andcopolymers thereof. Polyesters such as Poly(ethylene terephthalate)(PET), poly(ethylene terephthalate ionomer) (PETI), poly(ethylenenaphthalate) (PEN), poly(methylene naphthalate) (PTN), Poly(ButyleneTeraphalate) (PBT), poly(butylene naphthalate) (PBN), polycarbonate and.fluoropolymer such as Poly(tetrafluoroethylene), poly(methyldi-fluoroethyl siloxane), poly(methyl tri-fluoroethyl siloxane),poly(phenyl di-fluoroethyl siloxane).

In some embodiments, m and p are between 2 and 50 and n is between 2 and20. In certain embodiments, m and o are between 2 and 30 and n isbetween 2 and 20.

As defined generally above, each of L¹ and L² is independently abivalent C₁₋₂₀ hydrocarbon chain wherein 1-4 methylene units of thehydrocarbon chain are optionally and independently replaced by —O—, —S—,—N(R)—, —C(O)—, —C(O)N(R)—, —N(R)C(O)—, —SO₂—, —SO₂N(R)—, —N(R)SO₂—,—OC(O)—, —C(O)O—, or a bivalent cycloalkylene, arylene, heterocyclene,or heteroarylene, provided that neither of L¹ nor L² comprises a urea orurethane moiety. In some embodiments, each of L¹ and L² is independentlya bivalent C₁₋₂₀ alkylene chain. In certain embodiments, each of L¹ andL² is independently a bivalent C₁₋₂₀ alkylene chain. In certainembodiments, each of L¹ and L² is independently a bivalent C₁₋₆ alkylenechain. In certain embodiments, each of L¹ and L² is independently abivalent C₁₋₄alkylene chain. Exemplary such L¹ and L² groups includemethylene, ethylene, propylene, butylene or higher bivalent alkanes.

In some embodiments, each of L¹ and L² is independently a bivalent C₁₋₂₀alkylene chain wherein one methylene unit of the chain is replaced by—O—. In some embodiments, each of L¹ and L² is independently a bivalentC₁₋₁₀ alkylene chain wherein one methylene unit of the chain is replacedby —O—. In some embodiments, each of L¹ and L² is independently abivalent C₁₋₆ alkylene chain wherein one methylene unit of the chain isreplaced by —O—. In some embodiments, each of L¹ and L² is independentlya bivalent C₁₋₄ alkylene chain wherein one methylene unit of the chainis replaced by —O—. Exemplary such L¹ and L² groups include —OCH₂—,—OCH₂CH₂—, —OCH₂CH₂CH₂—, —OCH₂CH₂CH₂CH₂—, or higher bivalent alkyleneethers. In some embodiments, each of L¹ and L² is independently abivalent C₁₋₂₀ alkylene chain wherein at least one methylene unit of thechain is replaced by —O— and at least one methylene unit of the chain isreplaced by a bivalent arylene. In some embodiments, each of L¹ and L²is independently a bivalent Co alkylene chain wherein at least onemethylene unit of the chain is replaced by —O— and at least onemethylene unit of the chain is replaced by a bivalent arylene. In someembodiments, each of L¹ and L² is independently a bivalent C₁₋₆ alkylenechain wherein at least one methylene unit of the chain is replaced by—O— and at least one methylene unit of the chain is replaced by abivalent arylene. In some embodiments, each of L¹ and L² isindependently a bivalent C₁₋₄ alkylene chain wherein at least onemethylene unit of the chain is replaced by —O— and at least onemethylene unit of the chain is replaced by a bivalent arylene. Exemplarysuch L¹ and L² groups include —OCH₂-phenylene-, —OCH₂CH₂-phenylene-,—OCH₂CH₂-phenylene-CH₂—, —OCH₂CH₂CH₂CH₂-phenylene-, and the like.

One of ordinary skill in the art would understand that a polyurethaneresults from the reaction of a diisocyanate and a hydroxyl group.Similarly, a polyurea results from the reaction of a diisocyanate and anamine. Each of these reactions is depicted below.

Thus, it is readily apparent that provided compounds of formula I can befunctionalized with end groups suitable for forming urethane and/or urealinkages. In certain embodiments, the present invention provides acompound of formula II:

wherein:each of R^(x) and R^(y) is independently —OH, —NH₂, a protected hydroxylor a protected amine;each of X and Y is independently a polymer or co-polymer chain formedfrom one or more of a polyether, a polyester, a polycarbonate, and afluoropolymer;each of R¹, R², R³, R⁴, R⁵ and R⁶ is independently selected from one ormore of R, OR, —CO₂R, a fluorinated hydrocarbon, a polyether, apolyester or a fluoropolymer;each R is independently hydrogen, an optionally substituted C₁₋₂₀aliphatic group, or an optionally substituted group selected fromphenyl, 8-10 membered bicyclic aryl, a 4-8 membered monocyclic saturatedor partially unsaturated heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, or sulphur, or 5-6membered monocyclic or 8-10 membered bicyclic heteroaryl group having1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;each of m n and p is independently 2 to 100; andeach of L¹ and L² is independently a bivalent C₁₋₂₀ hydrocarbon chainwherein 1-4 methylene units of the hydrocarbon chain are optionally andindependently replaced by —O—, —S—, —N(R)—, —C(O)—, —C(O)N(R)—,—N(R)C(O)—, —SO₂—, —SO₂N(R)—, —N(R)SO₂—, —OC(O)—, —C(O)O—, or a bivalentcycloalkylene, arylene, heterocyclene, or heteroarylene, provided thatneither of L¹ nor L² comprises a urea or urethane moiety.

In some embodiments, each of X, Y, m, n, p, L¹, L², R¹, R², R³, R⁴, R⁵,and R⁶ is as defined and described herein.

As defined generally above, each of R^(x) and R^(y) is independently—OH, —NH₂, a protected hydroxyl or a protected amine. In someembodiments, both of R^(x) and R^(y) are —OH. In other embodiments, bothof R^(x) and R^(y) are —NH₂. In some embodiments one of R^(x) and R^(y)is —OH and the other is —NH₂.

In some embodiments, each of R^(x) and R^(y) is independently aprotected hydroxyl or a protected amine. Such protected hydroxyl andprotected amine groups are well known to one of skill in the art andinclude those described in detail in Protecting Groups in OrganicSynthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley &Sons, 1999, the entirety of which is incorporated herein by reference.Exemplary protected amines include methyl carbamate, ethyl carbamante,9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethylcarbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate,2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methylcarbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc),2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate(Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethylcarbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate,1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC),1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC),1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc),1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethylcarbamate, t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinylcarbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate(Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc),8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz),p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzylcarbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzylcarbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate,2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate,2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methylcarbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc),2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate(Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc),1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate,p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate,2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate,3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methylcarbamate, phenothiazinyl-(10)-carbonyl derivative,N′-p-toluenesulfonylaminocarbonyl derivative, N′-phenylaminothiocarbonylderivative, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzylcarbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentylcarbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate,2,2-dimethoxycarbonylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate,1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate,2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate,isobutyl carbamate, isonicotinyl carbamate,p-(p′-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate,1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate,1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate,1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate,p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate,4-(trimethylammonium)benzyl carbamate, 2,4,6-trimethylbenzyl carbamate,formamide, acetamide, chloroacetamide, trichloroacetamide,trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide,3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide,p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide,acetoacetamide, (N′-dithiobenzyloxycarbonylamino)acetamide,3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide,2-methyl-2-(o-nitrophenoxy)propanamide,2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide,3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethioninederivative, o-nitrobenzamide, o-(benzoyloxymethyl)benzamide,4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts),N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole,N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE),5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridone, N-methylamine, N-allylamine,N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine,N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammoniumsalts, N-benzylamine, N-di(4-methoxyphenyl)methylamine,N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr),N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr),N-9-phenylfluorenylamine (PhF),N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm),N2-picolylamino N′-oxide, N-1,1-dimethylthiomethyleneamine,N-benzylideneamine, N-p-methoxybenzylideneamine,N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine,N—(N′,N′-dimethylaminomethylene)amine, N,N′-isopropylidenediamine,N-p-nitrobenzylideneamine, N-salicylideneamine,N-5-chlorosalicylideneamine,N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine,N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine,N-borane derivative, N-diphenylborinic acid derivative,N-[phenyl(pentacarbonylchromium- or tungsten)carbonyl]amine, N-copperchelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide,diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt),diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzylphosphoramidate, diphenyl phosphoramidate, benzenesulfenamide,o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide,pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide,triphenylmethylsulfenamide, 3-nitropyridinesulfenamide (Npys),p-toluenesulfonamide (Ts), benzenesulfonamide,2,3,6,-trimethyl-4-methoxybenzenesulfonamide (Mtr),2,4,6-trimethoxybenzenesulfonamide (Mtb),2,6-dimethyl-4-methoxybenzenesulfonamide (Pme),2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte),4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide(Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds),2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide(Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide,4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS),benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

Exemplary hydroxyl protecting groups include methyl, methoxylmethyl(MOM), methylthiomethyl (MTM), t-butylthiomethyl,(phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM),p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM),guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM),siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl,bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR),tetrahydropyranyl (THP), 3-bromotetrahydropyranyl,tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl(MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranylS,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl(CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl,2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl,1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl,t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl,benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl,p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido,diphenylmethyl, p,p′-dinitrobenzhydryl, 5-dibenzosuberyl,triphenylmethyl, α-naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl,tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxyphenyl)diphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-tris(levulinoyloxyphenyl)methyl,4,4′,4″-tris(benzoyloxyphenyl)methyl,3-(imidazol-1-yl)bis(4′,4″-dimethoxyphenyl)methyl,1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl,9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl(TMS), triethylsilyl (TES), triisopropylsilyl (TIPS),dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS),dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl(TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl,diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate,benzoylformate, acetate, chloroacetate, dichloroacetate,trichloroacetate, trifluoroacetate, methoxyacetate,triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate,3-phenylpropionate, 4-oxopentanoate (levulinate),4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate,adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate,2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate,9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate(TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec),2-(triphenylphosphonio) ethyl carbonate (Peoc), alkyl isobutylcarbonate, alkyl vinyl carbonate alkyl allyl carbonate, alkylp-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzylcarbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzylcarbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzyl thiocarbonate,4-ethoxy-1-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate,4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl,4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate,2,6-dichloro-4-methylphenoxyacetate,2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate,o-(methoxycarbonyl)benzoate, α-naphthoate, nitrate, alkylN,N,N′,N′-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate,borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate,sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate(Ts). For protecting 1,2- or 1,3-diols, the protecting groups includemethylene acetal, ethylidene acetal, 1-t-butylethylidene ketal,1-phenylethylidene ketal, (4-methoxyphenyl)ethylidene acetal,2,2,2-trichloroethylidene acetal, acetonide, cyclopentylidene ketal,cyclohexylidene ketal, cycloheptylidene ketal, benzylidene acetal,p-methoxybenzylidene acetal, 2,4-dimethoxybenzylidene ketal,3,4-dimethoxybenzylidene acetal, 2-nitrobenzylidene acetal,methoxymethylene acetal, ethoxymethylene acetal, dimethoxymethyleneortho ester, 1-methoxyethylidene ortho ester, 1-ethoxyethylidine orthoester, 1,2-dimethoxyethylidene ortho ester, α-methoxybenzylidene orthoester, 1-(N,N-dimethylamino)ethylidene derivative,α-(N,N′-dimethylamino)benzylidene derivative, 2-oxacyclopentylideneortho ester, di-t-butylsilylene group (DTBS),1,3-(1,1,3,3-tetraisopropyldisiloxanylidene) derivative (TIPDS),tetra-t-butoxydisiloxane-1,3-diylidene derivative (TBDS), cycliccarbonates, cyclic boronates, ethyl boronate, and phenyl boronate.

One of ordinary skill in the art will appreciate that the choice ofhydroxyl and amine protecting groups can be such that these groups areremoved at the same time (e.g., when both protecting groups are acidlabile or base labile). Alternatively, such groups can be removed in astep-wise fashion (e.g., when one protecting group is removed first byone set of removal conditions and the other protecting group is removedsecond by a different set of removal conditions). Such methods arereadily understood by one of ordinary skill in the art.

In certain embodiments, the present invention provides a compound of anyof formulae II-a, II-b, II-c, and II-d:

wherein each of X, Y, m, n, p, L¹, L², R¹, R², R³, R⁴, R⁵, and R⁶ is asdefined and described herein.

Exemplary triblock copolymers of the present invention are set forthbelow:

wherein each of m, n, and p is as defined and described herein.

In some embodiments, the present invention provides a polymer foam,comprising:

-   -   (a) one or more triblock copolymers of formula I:

wherein each of X, Y, m, n, p, L¹, L², R¹, R², R³, R⁴, R⁵, and R⁶ is asdefined and described herein; and

-   -   (b) wherein the copolymers are chemically interspersed (bound)        between urethane and/or urea linkages (i.e., at the bond        designated with        ).

The invention further provides a pre-formed soft segment of the formulaI as defined above. In some embodiments, the present invention providesa polyurethane/urea foam comprising a soft segment triblock copolymer offormula I.

In some embodiments, the present invention provides a viscoelasticbiostable water blown foam, comprising:

-   -   (a) one or more triblock copolymers of formula I:

-   -   wherein each of X, Y, m, n, p, L¹, L², R¹, R², R³, R⁴, R⁵, and        R⁶ is as defined and described herein; and    -   (b) wherein the copolymers are chemically interspersed (bound)        between urethane and/or urea linkages (i.e., at the bond        designated with        ).

It has been surprisingly found that polyurethanes and/or polyureascomprising a triblock copolymer of the present invention are stable togastric fluid. Such polyurethanes and polyureas prepared using triblockcopolymers of the present invention are viscoelastic and stable togastric fluid. In some embodiments, a provided viscoelastic material isa foam.

In certain embodiments, a provided biostable foam is stable to gastricfluid. In some embodiments, a provided biostable foam is stable togastric fluid for at least one year. In some embodiments, a providedbiostable foam is stable to gastric fluid for at least 3 months, for atleast 4 months, for at least 5 months, for at least 6 months, for atleast 7 months, for at least 8 months, for at least 9 months, for atleast 10 months, for at least 11 months, or for at least one year.Methods for determining stability of a provided biostable foam are knownin the art utilizing simulated gastric fluid and include those describedin detail in the Exemplification, infra.

In some embodiments, a provided viscoelastic foam, comprising a triblockcopolymer of the present invention, is characterized in that the foamtakes up less than about 30% by weight of water at equilibrium. Incertain embodiments, a provided viscoelastic foam takes up less thanabout 5%, less than about 10%, less than about 15%, less than about 20%,less than about 25%, or less than about 30% by weight of water atequilibrium. One of ordinary skill in the art will appreciate that suchchemical stability (i.e., in gastric fluid and therefore at very low pH)and hydrophobicity (i.e., water uptake of less than about 30% by weight)are characterisitics that differ dramatically from known siloxanepolymers that are utilized in, e.g., the manufacture of contact lenses.For example, siloxane polymer that are utilized in, e.g., themanufacture of contact lenses require a water uptake of 50-120%.

As described above, the present invention provides a viscoelastic foamcomprising a triblock copolymer of the present invention. It wassuprisingly found that a provided foam has a high elongation capacityand the ability to recover very slowly following elongation. Indeed, itwas found that a provided viscoelastic foam has an elongation capacityof about 200-1200%. In some embodiments, a provided viscoelastic foamhas an elongation capacity of about 500%.

In some embodiments, a provided viscoelastic foam has a tensile strengthof about 0.1 to about 1.0 MPa. In certain embodiments, a providedviscoelastic foam has a tensile strength of about 0.25 to about 0.5 MPa.

In some embodiments, a provided viscoelastic foam has a Young's Modulusof about 0.1 to about 0.6 MPa. In certain embodiments, a providedviscoelastic foam has a Young's Modulus of about 0.1 to about 0.5 MPa.

One of ordinary skill in the art will appreciate that, depending uponthe physical characteristics required for a particular use of a providedfoam, a foam of varying densities can be prepared. For example, a valvehaving a thinner wall would require a foam having a higher density thana similar valve having a thicker wall in order to result in each valvehaving a similar physical characteristic (e.g., tensile strength, andthe like). Thus, in certain embodiments, a provided viscoelastic foamhas a density of 0.1 to 1.5 g/cm³. In certain embodiments, a providedviscoelastic foam has a density of 0.3 to 1.2 g/cm³. In certainembodiments, a provided viscoelastic foam has a density of 0.8 to 0.9g/cm³. In some embodiments, a provided viscoelastic foam has a densityof 0.5 to 0.6 g/cm³.

In certain embodiments, the present invention providespolyether-siloxane and polyether-fluorosiloxane polyurethane materialswith a greatly reduced number of weak-links as illustrated by FIG. 98and FIG. 99. This was achieved by preforming the soft segment prior tothe polyurethane reaction. In the examples below a triblock copolymerbased on polydimethyl siloxane and polypropylene oxide was used but itwill be appreciated that other triblock copolymers such as those formedfrom polysiloxanes and poly(ethylene oxide), poly(difluoromethylethylene oxide), poly(trifluoromethyl ethylene oxide), poly(propyleneoxide), poly(difluoromethyl propylene oxide), poly(propylene oxide),poly(trifluoromethyl propylene oxide), poly(butylene oxide),poly(tetramethylene ether glycol), poly(tetrahydrofuran),poly(oxymethylene), poly(ether ketone), poly(etherether ketone) andcopolymers thereof, poly(dimethylsiloxane), poly(diethylsiloxane) andhigher alkyl siloxanes, poly(methyl phenyl siloxane), poly(diphenylsiloxane), poly(methyl di-fluoroethyl siloxane), poly(methyltri-fluoroethyl siloxane), poly(phenyl di-fluoroethyl siloxane),poly(phenyl tri-fluoroethyl siloxane) and copolymers thereof,poly(ethylene terephthalate) (PET), poly(ethylene terephthalate ionomer)(PETI), poly(ethylene naphthalate) (PEN), poly(methylene naphthalate)(PTN), poly(butylene teraphalate) (PBT), poly(butylene naphthalate)(PBN) and polycarbonate could be used.

Referring to FIG. 98, copolymers of the form ABA, ABC and BAB wereproduced from homopolymers of polysiloxane and polypropylene oxide whichwere covalently linked using bonds less labile than urethane/urea. Themolecular weight and chemical characteristics of such homopolymers weretailored to achieve a pre-soft-segment with the appropriate balance ofhydrophilicity/hydrophobicity. Without wishing to be bound by anyparticular theory, it is believe that by using a non-urethane linkedtri-block copolymer instead of the constituent homopolymers as softsegments that the mechanical characteristics and hydrolytic stability ofthe resulting material is substantially improved.

In some embodiments, the present invention provides a foam comprising acopolymer of the present invention. Such foams offer specific advantagesover solid elastomers, especially for gastrointestinal deviceapplications. These advantages include enhanced biostability in thegastric environment, compressibility, viscoelasticity and high ‘surfacearea to volume ratio’. The foam formulations of the invention can mimicmechanical characteristics of the native gastrointestinal tissue.

A biostable water blown foam was prepared from heterogenous reagents.

The prior art describes polyurethane foams that are prepared by thesequential reaction of polymer chains to one another resulting in a highmolecular weight solid material. In all cases the polymeric precursorsdescribed in the art are linked together by urethane/urea linkages asillustrated in FIG. 97. However, each urethane/urea linkage is apossible site for degradation. In the invention we have prepared abiostable polyurethane/urea foam with much fewer ‘weak links’ by usingco-polymer precursors as shown in FIG. 98.

Polyurethane reactions have historically been carried out in a singlephase due to ease of processing. However, we have made novel materialsby combining physically heterogenous reaction pre-cursors together toform a stable two-phase dispersion (‘water-in-oil’) which was thenreacted to form a foam.

EXEMPLIFICATION

In two specific examples X and Y are both polyethers namelypoly(propylene oxide) (PPO). These were formulated into copolymers withpoly(dimethylsiloxane) (PDMS) and poly(trifluoropropyl methylsiloxane)respectively in varying ratios as described by the following formulae:

The formulations contained a number of other components including:

Branching Agent—DEOA

Diethanolamine (DEOA) is used as a branching agent although it issometimes known as a crosslinking agent. The molecular weight of DEOA is105.14 g/mol. The effect of the DEOA is to influence softness andelasticity of the end polymer.

Gelling Catalyst—Bismuth Neodecanoate (BICAT)

Bismuth neodecanoate is supplied as BiCat 8108M from Shepherd. It has amolecular weight of 722.75 g/mol. This catalyst is used to facilitatethe complete reaction between isocyanate and hydroyl or amine functionalgroups.

Blowing Catalyst—DABCO 33-Iv

DABCO is a common blowing catalyst for reaction between NCO and H₂O. Ithas a molecular weight of 112.17 g/mol. This catalyst has the effect, incombination with H₂O, of manipulating the foam rise characteristics.

Example 1 Synthesis of Aliphatic Linked Fluorosiloxane Based TriblockCopolymer Pre-Soft-Segment

This is a 2 step process. In the first step silanol terminatedpoly(trifluoropropyl methyl siloxane) is converted into its dihydridederivative. In the next step, this dihydride derivative is reacted withthe allyl terminated poly(propylene glycol).

The synthetic procedure is as follows:

Step 1

To a 4 neck separable flask fitted with mechanical stirrer, was added 40g of Silanol terminated poly(trifluoropropyl methylsiloxane) (FMS-9922from Gelest Inc.) and this was mixed with 50 ml of toluene and fittedwith a continuous flush of Nitrogen. To the reaction mixture 7.57 g ofdimethyl chlorosilane (DMCS, from Sigma Aldrich) was added slowly overabout 20 minutes keeping the temperature of the mixture constant at 30°C. With each addition of dimethyl chlorosilane, the mixture became hazybut cleared in a short period of time. Once the addition of dimethylchlorosilane was complete, the mixture was heated to 90° C. for 3 hours.The reaction was then washed with excess water several times to reducethe acidity of the mixture. The resulting mixture was dried over silicagel, filtered and vacuumed to remove solvent and traces of water at 65°C. overnight. A clear fluid was then obtained with a very strong Si—Hband in infra red spectroscopy (IR) at 2130 cm⁻¹, which confirms thereaction. GPC analysis showed the molecular weight to be 1200 g/mol.

Step 2.

To 90 ml of reagent grade toluene in a 4 neck separable flask fittedwith mechanical stirrer, 46.67 g of Allyl terminated poly(propyleneglycol) (MW=700 g/mol, Jiangsu GPRO Group Co.) was added and then heatedto reflux. Then 40 g of Hydride terminated FMS-9922 was dissolved in 50ml of reagent grade toluene and the temperature raised to around 90° C.To the reaction mixture 2 drops of hexachloroplatinic(IV) acid (0.01MH₂PtCl₆ from Sigma) solution in isopropanol (by Merck) was then added.After this catalyst solution had been added, the mixture was refluxedfor 1 hour and the solvent distilled off in order to get the finalproduct. The reaction was followed by H-NMR and gel permeationchromatography (GPC) confirmed the final molecular weight to be 2700g/mol.

TABLE 1 Resulting polymer block ratios Stoiciometric ratios for reactionproduct: Polymer block PO F-SiO PO m n p Ratio 11 9.7 11

Example 2 Synthesis of Aliphatic Linked Dimethylsiloxane Based TriblockCopolymer Pre-Soft-Segment

To 130 ml of reagent grade toluene in a separable flask fitted with amechanical stirrer, was added 64 g of allyl terminated poly(propyleneglycol) (MW=700 g/mol, Jiangsu GPRO Co.) and both were mixed and heatedto reflux. Then 40 g of hydride terminated poly(dimethyl siloxane)(Silmer H Di 10 by Siltech Corp.) was dissolved in 50 ml reagent gradetoluene and the temperature raised to around 90° C. To this reactionmixture 2 drops of hexachloroplatinic(IV) acid (0.01M H₂PtCl₆ fromSigma) solution in isopropanol was added. After this catalyst solutionwas added, the mixture was refluxed for 1 hour and then the solvent wasdistilled off in order to get the final product. The reaction wasfollowed with H-NMR and gel permeation chromatography (GPC) confirmedthe final molecular weight of the product to be 2300 g/mol.

TABLE 2 Polymer block ratios Stoiciometric ratios for reaction product:Polymer block PO SiO PO m n p Ratio 11 11 11

Example 3 Synthesis of Aromatic Linked Siloxane Based Triblock CopolymerPre-Soft-Segment

To a 100 ml separable flask fitted with a mechanical stirrer, 15 g ofhydroxy terminated polydimethyl siloxane (DMS-S14 from Gelest Inc.) wasadded along with 5.36 g of di-chloro p-xylene (from Sigma) and 0.0089 gof Copper(II) acetylacetonate (Cu(Acac)₂ from Sigma). The reactionmixture was refluxed at 110° C. for 5 hrs. At this point, 19.77 g ofhydroxy terminated poly(propylene glycol) (from Sigma) was addeddropwise and the reaction mixture was then refluxed for another 15 hr.The progress of reaction was followed by ¹H-NMR and the final molecularweight, determined by gel permeation chromatography (GPC), was 3000g/mol.

H-NMR analysis: Solvent used for ¹H-NMR analysis is CDCl₃.

Aromatic H=7.25-7.45 ppm, —CH₂=4.5-4.6 ppm, —CH₃ (of PPO)=1-1.4 ppm,—CH₂ (of PPO)=3.2-3.8 ppm, —OH (of PPO)=3.8-4 ppm, —CH₃(silanol)=0.5-0.8 ppm.

TABLE 3 Resulting polymer block ratios Stoiciometric ratios for reactionproduct: Polymer block PO SiO PO m n p Ratio 14 15.5 14

Example 4 Synthesis of Aromatic Linked Fluorosiloxane Based TriblockCopolymer Pre-Soft-Segment

To a 100 ml separable flask fitted with a mechanical stirrer, 15 g ofhydroxy terminated polytrifluoromethyl siloxane (FMS-9922, Gelest inc.)was added along with 5.9 g of di-chloro p-xylene and 0.0098 g ofcopper(II) acetylacetonate (Cu(Acac)₂ from Sigma). The reaction mixturewas refluxed at 110° C. for 5 hrs. At this point, 21.75 g of hydroxyterminated poly(propylene glycol) (from Sigma) was added dropwise to thereaction mixture. The reaction was refluxed for another 15 hr. Theprogress of reaction was followed by ¹H-NMR analysis and the molecularweight, determined by gel permeation chromatography (GPC), was 3100g/mol.

¹H-NMR analysis: Solvent used for H-NMR analysis is CDCl₃.

Aromatic ¹H=7.25-7.45 ppm, —CH₂=4.5-4.6 ppm, —CH₃ (of PPO)=1-1.4 ppm,—CH₂ (of PPO)=3.2-3.8 ppm, —OH (of PPO)=3.8-4 ppm, —CH₃(silanol)=0.5-0.8 ppm.

TABLE 4 Polymer block ratios Stoiciometric ratios for reaction product:Polymer block PO FSiO PO m n p Ratio 14 9.2 14

Example 5 Preparation of Water Blown Foam

The pre-soft segments prepared can be described as having polymer blockratios which are numerically represented by the letters m, n and o forthe constituents PO/SiO/PO respectively. The triblock copolymersprepared in Examples 1 and 2 with specific m, n, o ratios wereformulated into polyurethane/urea foams as illustrated by Table 7.

The process for preparing the foam was a two-step procedure. Thefollowing describes the method of manufacture of the first product inTable 7. The same procedure was used to prepare other foams as describedby Table 8.

-   Step 1) Firstly a mixture was made with 0.041 g of DABCO LV-33    (Airproducts), 0.120 g of bismuth neodecanoate (Bicat 8108M from    Shepherd chemicals), 0.467 g of diethanol amine (DEOA, from Sigma),    7.917 g of synthesized block copolymer, 0.200 g water and 0.1 g of    surfactant (Niax L-618 from Airproducts) in a plastic flat bottomed    container. This is then thoroughly mixed manually for 30 sec until a    homogenous mixture was obtained.-   Step 2) To the above mixture, 15 g of a diisocyanate prepolymer (PPT    95A Airproducts) was added. This was then thoroughly mixed by a    mechanical stirrer for about 5 seconds. The material was then molded    and cured at 70° C. for 2.5 hours and post cured at 50° C. for    another 3 hours.

TABLE 5 Formulation details for foam Polymer block Formulation(PO/SiO/PO) Identification Ratio m:n:p DABCO BICAT DEOA H₂O VF230209A11:11:11 0.0325 0.015 0.40 1.0 VF090309B 11:9:11 0.0325 0.015 0.40 1.0

Example 6 Comparative Example of Formulation of Water Blown Foam fromTriblock Copolymer Pre-Soft Segment and Individual Homopolymers

Polyurethane/urea polymer foams from Example 5 were compared to foamsmade from the stoichiometric equivalent homopolymer soft segments. Thefoams with homopolymer based soft segments (VF130309 and VF190309) shownin FIG. 100 were produced as follows (VF130309):

-   Step 1) Firstly a mixture was made with 0.041 g of DABCO LV-33    (Airproducts), 0.120 g of bismuth neodecanoate (Bicat 8108M from    Shepherd chemicals), 0.467 g of diethanol amine (DEOA, from Sigma),    3.056 g of poly(dimethyl siloxane) diol (DMS-s14 Gelest Inc.), 1.633    g of polypropylene oxide (Mw=700 g/mol), 0.200 g water and 0.1 g of    surfactant (Niax L-618 from Airproducts). These were added to a    plastic flat bottomed container and were thoroughly mixed manually    for 30 sec until a homogenous mixture was obtained.-   Step 2) To the above mixture, 15 g of a diisocyanate prepolymer (PPT    95A Airproducts) was added. This was then thoroughly mixed by a    mechanical stirrer for 5 seconds. The material was then molded and    cured at 70° C. for 2.5 hours and post cured at 50° C. for another 3    hours.

The foams in this example were made into dumbbell shapes for tensiletesting. FIGS. 100 and 101 illustrate the difference in mechanicalbehaviour between the comparative materials indicating a favourablelowering in modulus for the triblock copolymer pre-soft-segments.

Example 7 Comparative Stability of Triblock Copolymer Soft SegmentVersus Homopolymer Soft Segment

Tensile test specimens were prepared in the same manner to the materialsused in Example 4 and were subjected to accelerated aging in simulatedgastric fluid (as per United States Pharmacopeia, “USP”). The materialsproduced with the pre-synthesised triblock copolymer soft segmentsresulted in substantially improved mechanical stability in gastric fluidas compared to the urethane/urea linked homopolymer equivalent asillustrated in FIG. 90. This facilitates the use of such materials forprolonged periods in digestive and more specifically gastricenvironments.

Example 8 Preparation of Water Blown Foams

Several water blown polyurethane/urea foams were also produced withvarying PO/EO/SiO polymer block ratios. The process for preparing thefoam as described above was used.

TABLE 6 Water blown formulations incorporating siloxane containingcopolymer pre-soft-segments. Polymer block ratio (PO/EO/SiO) m:n:p DABCOBICAT DEOA H₂O 41.5:8.3:0.5 0.114 0.022 0.22 2.72 40.2:7.8:0.5 0.1140.022 0.22 2.72 37.5:7:0.5 0.114 0.022 0.22 2.72 33.5:5.7:0.5 0.1140.022 0.22 2.72 29.6:4.4:0.5 0.114 0.022 0.22 2.72 21.6:1.8:0.5 0.1140.022 0.22 2.72 19:1:0.5 0.114 0.022 0.22 2.72 29.6:4.5:1.1 0.114 0.0220.22 2.72

The results from the formulations described in Table 6 are shown inTable 7.

TABLE 7 Results from mechanical testing of foams from Table 5 Polymerblock ratio (PO/EO/SiO) m:n:p % Elongation Tensile Strength (N)41.5:8.3:0.5 233 0.46 40.2:7.8:0.5 243 0.31 37.5:7:0.5 237 0.333.5:5.7:0.5 260 0.23 29.6:4.4:0.5 320 0.23 21.6:1.8:0.5 497 0.2319:1:0.5 462 0.22 29.6:4.5:1.1 437 0.29

Example 9 Use Example

Devices for use in the gastrointestinal system have historically notbeen made from specifically designed materials. Off the shelf materialsused for application in the corrosive environment of the stomach havelimited biostability and generally lose their functionality after ashort time.

The foam of the invention can be used for production of a valve of thetype described in our US2007-0198048A, the entire contents of which areincorporated herein by reference. The valve has an open position and aclosed position. The valve will have a proximal end and a distal end.The valve material can open from the proximal direction when the actionof swallowing (liquid or solid) stretches an orifice by between 100% and3000% in circumference. The open orifice optionally closesnon-elastically over a prolonged period of time, thus mimicking thebody's natural response. The duration taken to close may be between 2and 15 sec. The material can stretch to between 100%-300% from thedistal direction when gas, liquid or solids exceeds a pre-determinedforce of between 25 cmH₂O and 60 cmH₂O. In some embodiments, thematerial absorbs less than 15% of its own mass of water at equilibrium.In some embodiments, the material loses (leaches) less than 3% of it'sown mass at equilibrium in water or alcohol. In some embodiments, thematerial loses less than 10% of its tensile strength when immersed in asimulated gastric fluid at pH 1.2 for 30 days. In some embodiments, thevalve material loses less than 25% of its % elongation when immersed ina simulated gastric fluid at pH 1.2 for 30 days.

Example 10 Valve Functional Testing

The healthy lower esophageal sphincter (LES) remains closed until anindividual induces relaxation of the muscle by swallowing and thusallowing food to pass in the antegrade direction. Additionally when anindividual belches or vomits they generate enough pressure in thestomach in the retrograde direction to overcome the valve. Ananti-reflux valve must enable this functionality when placed in thebody, thus a simple functional test is carried out to asses performance.

It has been reported that post fundoplication patients have yieldpressures between 22-45 mmHg and that most of the patients with gastricyield pressure above 40 mmHg experienced problems belching. See Yieldpressure, anatomy of the cardia and gastro-oesophageal reflux. Ismail,J. Bancewicz, J. Barow British Journal of Surgery. Vol: 82, 1995, pages:943-947. Thus, in order to facilitate belching but prevent reflux, anabsolute upper GYP value of 40 mmHg (550 mmH₂O) is reasonable. It wasalso reported that patients with visible esophagitis all have gastricyield pressure values under 15 mmHg, therefore, there is good reason toselectively target a minimum gastric yield pressure value that exceeds15 mmHg. See Id. An appropriate minimum gastric yield pressure valuewould be 15 mmHg+25% margin of error thus resulting in a minimumeffective valve yield pressure value of 18.75 mmHg or 255 mmH₂O.

The test apparatus consists of a 1 m high vertical tube as shown in FIG.103, to which is connected a peristaltic pump and a fitting that isdesigned to house the valve to be tested.

The valve to be tested is placed in a water bath at 37° C. for 30minutes to allow its temperature to equilibrate. Once the temperature ofthe valve has equilibrated it is then installed into the housing suchthat the distal closed end of the valve faces the inside of the testapparatus. The pump is then switched on at a rate of 800 ml/min to beginfilling the vertical tube. The rising column of water exerts a pressurethat forces the valve shut initially. As the pressure in the columnrises the valve reaches a point where it everts and allows the water toflow through. This point, known as the yield pressure, is then recordedand the test repeated four times.

Example 11 Rationale for Accelerated Aging of Material

Clinical Condition being Simulated

The lower oesophagus of a normal patient can be exposed to the acidiccontents of the stomach periodically without any adverse side effects.However, patients with gastro esophageal reflux disease experiencedamage to the mucosa of the lower oesophagus due to increased exposureto the gastric contents. Exposure of the lower oesophagus to acidicgastric contents is routinely measured in the clinic using dedicated pHmeasurement equipment. A typical procedure involves measuring pH over a24-hour period. The levels of acid exposure in pathological refluxdisease patients is summarised in Table 8 from six clinical references.See DeMeester T R, Johnson L F, Joseph G J, et al. Patterns ofGastroesophageal Reflux in Health and Disease Ann. Surg. October 1976459-469; Pandolfino J E, Richter J E, Ours T, et al. AmbulatoryEsophageal pH Monitoring Using a Wireless System Am. J. Gastro 2003;98:4; Mahmood Z, McMahon B P, Arfin Q, et al. Results of endoscopicgastroplasty for gastroesophageal reflux disease: a one year prospectivefollow-up Gut 2003; 52:34-9; Park P O, Kjellin T, Appeyard M N, et al.Results of endoscopic gastroplasty suturing for treatment of GERD: amulticentre trial Gastrointest endosc 2001; 53:AB115; Filipi C J, LehmanG A, Rothstein R I, et al. Transoral flexible endoscopic suturing fortreatment of GERD: a multicenter trial Gastrointest endosc 2001; 53416-22; and Arts J, Slootmaekers S Sifrim D, et al. Endoluminalgastroplication (Endocinch) in GERD patient's refractory to PPI therapyGastroenterology 2002; 122:A47.

TABLE 8 Summary of acid exposure in patients with reflux diseaseInvestigator Number of patients Details %24 h < pH 4 DeMeester 54Combined refluxers 13.5 Pandolfino 41 Gerd 6.5 Mahmood 21 Gerd 11.11Park 142 Gerd 8.5 Filipi 64 Gerd 9.6 Arts 20 Gerd 17 Average 11.035

Key Clinical Parameters

Considering that the lower oesophagus is exposed to the acidic pHexposure time for an average of 11% of the measurement period, anaccelerated aging methodology can easily be conceived. Constant exposureof a test material to the gastric contents (or USP Simulated GastricFluid—Reference USP Pharmacopeia) would represent an almost 10-foldincrease in the rate of aging. Thus the time required to simulate oneyear of exposure of the lower oesophagus to the gastric contents isdescribed by equation 1.

$\begin{matrix}{{\left( \frac{11.035}{100} \right) \times 365\mspace{14mu} {days}} = {40.28\mspace{14mu} {days}}} & {{Equation}\mspace{14mu} 1}\end{matrix}$

Clinical Rationale

Immersion of test specimens in USP Simulated gastric fluid for 40.27days at 37° C. will approximate one year's exposure of the loweroesophagus to acidic gastric contents in a GERD patient's scenario.

Simulated Exposure Real Time 1 year  40.28 days 2 years 80.56 days 3years 120.84 days 

Results of accelerated stability of a valve prepared from a viscoelasticfoam of the present invention are depicted in FIGS. 104 and 105.

While we have described a number of embodiments of this invention, it isapparent that our basic examples may be altered to provide otherembodiments that utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments that have been represented by way of example.

Various features of the invention are described in detail andillustrated herein. Appropriate features described with reference to oneembodiment may be utilised in addition to and/or as a substitute forfeatures described in other embodiments.

The invention is not limited to the embodiments hereinbefore describedwhich may be varied in detail.

1. A urological device comprising:— a urological valve for location inthe bladder of a patient; and a valve support stem for location in theurethra of a patient, the valve having a normally closed configurationto prevent flow from the bladder and an open configuration for fluidflow through the valve, the valve being automatically movable from theclosed configuration to the open configuration in response to a pre-sethydrodynamic pressure applied for a pre-set time.
 2. A urological deviceas claimed in claim 1 wherein the valve support stem comprises agenerally tubular support for extending at least partially through theurethra, the valve being located at one end of the support.
 3. Aurological device as claimed in claim 1 comprising a bladder retainerfor locating the valve in the bladder.
 4. A urological device as claimedin claim 3 wherein the bladder retainer comprises a flare extendingradially outwardly of the support stem.
 5. A urological device asclaimed in claim 4 wherein the bladder retainer is of the same materialas that of the support.
 6. A urological device as claimed in claim 5wherein the bladder retainer, the support and the valve are integrallymoulded.
 7. A urological device as claimed in claim 3 comprisingstiffening means for the bladder retainer.
 8. A urological device asclaimed in claim 7 wherein the bladder retainer stiffening means is of ashape memory material such as Nitinol.
 9. A urological device as claimedin claim 1 comprising a urethral retainer to prevent migration of thedevice.
 10. A urological device as claimed in claim 9 wherein theurethral retainer comprises a metal tab.
 11. A urological device asclaimed in claim 9 wherein the urethral retainer comprises a bulbousregion of compressive material.
 12. A urological device as claimed inclaim 1 wherein the valve the valve is of a viscoelastic polymeric foammaterial.
 13. A urological device as claimed in claim 1 wherein thevalve comprises a plurality of valve leaflets, the valve having a regionof co-aption between the valve leaflets, the valve leaflets beingengaged at the region of co-aption in the normally closed configurationand the leaflets being separated at the co-aption region in the openconfiguration for fluid flow through the valve.
 14. A urological deviceas claimed in claim 13 wherein the valve leaflets evert on movementbetween the closed and the open configuration in response tohydrodynamic pressure.
 15. A urological device as claimed in claim 1wherein the valve is adapted to open in response a hydrodynamic pressureof at least 750 mm H₂O applied for at least 5 seconds.
 16. A urologicaldevice as claimed in claim 1 wherein the valve is adapted to remainclosed in response to a spike pressure applied for a short time as wouldbe generated by a user coughing.
 17. A urological device as claimed inclaim 16 wherein the spike pressure is 900 mm H₂O applied for a periodof less than 0.5 seconds.
 18. A urological device as claimed in claim 1wherein the valve remains open as fluid flows therethrough without arequirement for a user to apply urological pressure.
 19. A urologicaldevice as claimed in claim 1 wherein the valve returns to the closedconfiguration when flow through the valve has substantially stopped. 20.A urological device as claimed in claim 1 wherein the valve everts onmovement from the closed to the open configuration.
 21. A urologicaldevice as claimed in claim 20 wherein the valve reverts on return fromthe open to the closed configuration.
 22. A urological device as claimedin claim 1 wherein the valve comprises at least three valve leaflets.23. A urological device as claimed in claim 1 wherein the valvecomprises a main body having a region which defines a hinge about whichportion of the valve main body is movable between the closed and openconfigurations.
 24. A urological device as claimed in claim 23 whereinthe valve comprises stiffening means.
 25. A urological device as claimedin claim 24 wherein the hinge region is at least partially definedadjacent to the stiffening means.
 26. A urological device as claimed inclaim 1 wherein the device comprises an antimicrobial coating.